AU2016267585B2

AU2016267585B2 - Stable cannabinoid formulations

Info

Publication number: AU2016267585B2
Application number: AU2016267585A
Authority: AU
Inventors: Venkat R. Goskonda; Huaguang Li; Hung Q. Nguyen; Kiran Kumar Vangara; Ningxin YAN
Original assignee: Radius Pharmaceuticals Inc
Current assignee: Radius Pharmaceuticals Inc
Priority date: 2015-05-28
Filing date: 2016-05-27
Publication date: 2021-12-16
Anticipated expiration: 2036-05-27
Also published as: WO2016191651A1; DK3302437T3; JP6899506B2; JP7374951B2; EP3302437A4; CA2986268C; EP3302437B1; AU2022201441A1; EP3302437B8; CA2986268A1; AU2016267585A1; ES2938560T3; EP3302437A1; JP2018516281A; EP4193990A1; AU2016267585C1; JP2021107438A

Abstract

The present invention is generally directed to substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of their use.

Description

STABLE C ANN A B I NO ID FORMULATIONS

Priority

[0001] This application claims priority to U.S. Patent Application No. 14/724,351 , filed May 28, 2015 and U.S. Provisional Patent Application Nos. 62/004,495, filed May 29, 2014, and 62/154,660, filed April 29, 2015. The entire contents of each applicadon is incorporated herein by reference.

Field of the Inv ntion

[0002] The present invention is generally directed to substantially pure cannabidiol, stable eannabinoid pharmaceutical formulations, and methods of their use.

Background

[0003] Cannahinoids are chemicals that are produced by cannabis flowers.

Cannabmoids imitate endogenous compounds in humans.

[0004] Cannabmoids include cannabinol, cannabidiol, dronabinol (delta-9- tetrahydrocannabinol), delta-8-tetrahydrocannabinoL 1 1 -hydroxy- tetrahydrocannabinol, 1 l-hydroxy-delta9-tetrahydrocannabinol, !evonantradoi, delta- 1 1 -tetrahydrocannabinol, tetrahydrocannabivarin, amandamide, nabilone, and acids and analogs thereof. It is now possible to synthesize many cannabinoids in a laboratory thereby eliminating the need to grow cannabis for extraction of the compounds.

[0005] One eannabinoid, cannabidiol, (-)-trans-2-p~mentha-l ,8-di6n-3~yl-5- pentylresoreinoL is non-psychoactive and has shown promise in treating numerous diseases and disorders. Synthetic cannabidiol has the same structure as naturally occurring cannabidiol.

[0006] Commercially available cannabidiol. is usually contaminated with delta 9- tetrahydrocannabinol. The presence of delta-9-tetrahydrocamiabinol can be a concern because delta-9-tetra ydrocannabinol is regulated by the United States Drug Enforcement Administration as a Schedule ί Drug. Having a higher Schedule number could result in easier access for patients to cannabidiol treatments. Further, delta-9- ieirahydrocannabinol is a hallucinogen and patients receiving cannabidiol wish to avoid this undesirable side effect of the delta-9-tetrahydrocannabinol contaminant. Therefore, there is a need for a substantially pure synthetically synthesized cannabidiol thai does not contain delta-9-ietrahydrocannabinol.

[0007J Cannnabtnoids, including cannabidiol, may be suitable for the treatment of diseases or disorders, or symptoms of diseases or disorders, such as Dravet Syndrome, Lennox Gastaut Syndrome, mycoionic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, refractory infantile spasms, infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's Disease, autism, and withdrawal from opioids, cocaine, heroin, amphetamines, and nicotine.

[0008] Accordingly, there is a need for new stable cannabinoid formulations.

There is also a need for substantially pure cannabidiol.

Summary of the Inve ii n

[0009] In one aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40 % of a cannabinoid and from about 10 to about 95 % of a lipid.

[00010] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40 % of a cannabinoid and from about 10 to about 95 % of a lipid wherein the formulation is free of alcohol.

[00011] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about about 15 % efhano!.

0Θ012] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40 % of a cannabinoid, from about 10 to about 95 % of a lipid and from about 0.001 % to about 1 % of an antioxidant,

[00013] in another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 5 to about 40 % of eannabidiol and from about 10 to about 74 % medium chain glyceride.

[00014] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40 % of eannabidiol and from about 10 to about 74 % medium chain glyceride wherein die formulation is free of alcohol,

[00015] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0.1 to about 40 % of eannabidiol, from about 10 to about 74 % caprylic/capric triglyceride and from about 1 % to about 15 % efhanoi.

[00016] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 0,1 to about 40 % of eannabidiol, from about 10 to about 74 % medium chain glyceride and from about 0.1 % to about 1.0 % of an antioxidant selected from the group consisting of alpha- tocopherol (Vitamin E). ascorbyl palmitate and a combination thereof.

[00017] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising from about 28 % to about 32 % of eannabidiol and from about 66% to about 74 % medium chain glyceride.

[00018] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising about 31 .09 %.

[00019] In another aspect, the present invention is directed to stable pharmaceutical formulations for oral administration comprising about 31 .09 % and ethanol. [00020] In another aspect, the invention is directed to methods of using formulations of the invention to treat or prevent diseases or disorders, or treat symptoms of diseases or disorder selected from the group consisting of Prader-Willi syndrome, obesity, graft, versus host disease, gelastic seizures/hypothalamic hamartoma, neonatal seizures, movement disorders including dystonia, central pain syndromes, phantom limb pain, multiple sclerosis, traumatic brain injury, radiation therapy, acute and chronic graft versus host disease, T-cell autoimmune disorders, colitis, Dravet Syndrome, Lennox Gastaut Syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's Disease, autism, acne, Parkinson's disease, social anxiety disorder, depression, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, ischemic injury of heart, ischemic injury of brain, chronic pain syndrome, rheumatoid arthritis.

[00021] In another aspect, compositions of the present invention are administered to a patient that is in a fed or fasted condition.

[00022] In another aspect, the invention is directed to methods of using formulations of the invention for assisting with withdrawal from opioids, cocaine, heroin, amphetamines and nicotine; and as an analgesic or to assist with handling of adverse emotional stimuli.

Brief Description of the Figures

[00023] Fig. 1 shows the results from the study detailed in Example 7 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidioi formulations for treatment of neuropathic pain.

[00024] Fig. 7 shows the results from the study detailed in Example 14 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidioi formulations for treatment of glioblastoma multiforme.

[00025] Fig. 2 shows the results from the study detailed in Example 8 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations over THC formulations for treatment of neuropathic pain.

[00026] Fig, 3 shows further results from the study detailed in Example 8 and illustrates dose-dependent advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations over THC formulations for treatment of neuropathic pain.

[0Θ027] Fig. 4 shows further results from the study detailed in Example 8 and illustrates synergistic results of administration of substantially pure, synthetically synthesized, cannabidiol formulations and THC formulations for treatment of neuropathic pain.

[00028] Fig. 6 shows the results from the study detailed in Example 10 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations for treatment of neuropathic pain,

[00029] Fig, 5 shows the results from the study detailed in Example 9 and illustrates the advantages administration of higher ratio substantially pure, synthetically synthesized, cannabidiol to THC formulations for treatment of neuropathic pain,

[00030] Fig. 8 shows the results from the study detailed in Example 15 and illustrates the advantages of administration of substantially pure, synthetically synthesized, cannabidiol formulations for treatment of glioblastoma multiforme.

Detailed Description

[00031] As indicated above, Applicant created stable formulations with and without alcohol (see Examples 1 and 3). The formulations that do not contain alcohol are especially suitable for administration to children. Further, the alcohol-free formulations are especially suitable for patients in recovery from drug and alcohol addiction.

[00032] in addition. Applicant created stable lipid formulations (see Example 5).

These formulations were also unexpectedly stable during storage (see Example 6).

[G0033J Further, Applicant unexpectedly found that substantially pure cannabidiol formulations are especially suitable for treatment of neuropathic pain (see Examples 7-10 and Figs, 1 -6). epilepsy (see Examples 1 1-13), and glioblastoma multiforme (see Examples 14 and 15 and Figs. 7 and 8).

Alcohol -Free Formulations

[00034] In one embodiment, the present invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 50 % of a cannabinoid, from about 0.1 to about 40 % of a polyethylene glycol, from about 0.1 to about 50 % of propylene glycol, and from about 0.1 to about 20 % of water, wherein die formulation does noi contain alcohol and the formiiiation has a pR of from about 5 to about 8.

[00035] In a preferred embodiment, the formulations contain from about 1 to about

40 % of a cannabinoid. In more preferred embodiments, the formulations contain from about. 5 to about 35 %, from about 20 to about 35 % or from about 30 to 35 % of a cannabinoid.

[00036] In yet. another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, eannabidiol, dronabinol (deita-9- tetrahydrocannabinol), deIta-8-tetrahydrocamiabinol, 1 1 -hydro y-tetrahydrocannabinol, 1 1 -hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta- 1 1 "tetrahydrocannabinol, tetrahydrocannabivarin, amandanvide. nabilone, acids, analogs, and synthetic derivatives thereof, in a preferred embodiment, the cannabinoid is eannabidiol.

[00037] in a preferred embodiment, the formulations contain from about 1 to about

40 % of a eannabidiol. In more preferred embodiments, the formulations contain from about 5 to about 35 , from about 20 to about 35 % or from about 30 to 35 % of a eannabidiol.

[00038] in yet another embodiment, the formulations contain eannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98 %. In a more preferred embodiment, the eannabidiol is greater than 99 % pure. In an even more preferred embodiment, the eannabidiol is greater than 99.5 % pure. In a most preferred embodiment, the eannabidiol formulation contains less than 0.3 % delta-9- ietrahydrocannabinol. [00039] In another embodiment, the formulations contain from about 0.001 to about 1 % of an antioxidant. In a preferred embodiment, the formulations contain from about 0.01 to about 1 % antioxidant. In a more preferred embodiment, the formulations contain from about 0,02 to about 0.5 % antioxidant.

[0Θ040] Suitable antioxidants include buiylated hydroxyl toluene ("BHT"), buiylated hydroxyl anisoie ("BHA"), alpba-tocophero! (Vitamin E), ascorbyl paimitate, ascorbic acid, sodium aseorbate, ethylenediamino tetraacetic acid, cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, monothioglyceroS lert-but lh droquino e ("TBHQ") and combinations thereof. In a preferred embodiment, the formulations contain alpha-tocopherol (Vitamin E), ascorbic acid, sodium aseorbate, ascobyl paimitate or combinations thereof,

[00041] in another embodiment, the formulations contain from about 1 to about

40 % of a polyethylene glycol Jn a preferred embodiment, the formulations contain from about 1 to about 35 %, from about 5 to about 35 %, from about 20 to about 30 %, or from about 25 to about 30 % polyethylene glycol

[00042] Suitable polyethylene glycols include low molecular weight polyethylene glycols with an average molecular weight of between 200 and 1.0,000. One preferred polyethylene glycol that can be used is polyethylene glycol 400.

[00043] In another embodiment, the formulations contain from about 1 to about

40 % of polyethylene glycol 400. In a preferred embodiment, the formulations contain from about 1 to about 35 %, from about 5 to about 35 %, from about 20 to about 30 %, or from about 25 to about 30 % polyethylene glycol 400.

[00044] In another embodiment, the formulations contain from about 1 to about

50 % of propylene glycol In a preferred embodiment, the formulations contain from about 1 to about 40 '¾, from about 5 to about 35 %, from about 20 to about 35 %, or from about 30 to about 35 % propylene glycol

[00045] in a further embodiment, the formulations contain water, The formulations can contain 0 % water. If the formulations contain water, they can include from about 1 to about 15 % water, from about 1 to about 10 % water, or from about 4 to about 8 % water.

[00046] The pH of the formulations may be modified using any pharmaceutically acceptable means, Preferably the pH of the formulation is from about 5 to about 8. In a more preferred embodiment, the pH of the formulations is from about 6 to about 7. in a most preferred embodiment, the pH of the formulations is from about 6.2 to about 6,7.

[00047] The formulations of the present invention may also contain sweeteners, sweetener enhancers, preservatives, pH modifiers, and flavoring agents.

[00048] Suitable sweeteners include, but are not limited to, sucrose, aspartame, saccharin, dextrose, mannitoi, xylitol, and combinations thereof.

[00049] If the formulations contain a sweetener, the formulations preferably contain from about 0.001 to about 1 % sweetener.

[00050] if the formulations contain a sweetness enhancer, the formulations preferably contain from about 0.001 to about 1% sweetness enhancer.

[00051] Suitable sweetness enhancers include, but are not limited to, the ammonium salt forms of crude and refined Glycyrrhizic Acid. Magnasweet^® products (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation) use the ammonium salt forms of crude and refined Glycyrrhizic Acid. Glycyrrhizic Acid is also available as a pure derivative in the sodium and potassium salt forms.

[00052] Suitable pH modifiers include, but are not limited to, hydrochloric acid, ascorbic acid, citric acid, sodium citrate, funiaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, and combinations thereof.

[00053] Suitable preservatives include, but. are not Limited to, methyl paraben. propyl paraben, benzyl alcohol, benzoic acid, sodium benzoate, sorbic acid, and combinations thereof.

[00054] Suitable flavoring agents include, but are not limited to, raspberry, peppermint oil, grape flavor, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, lemon oil, lemon mint flavor, fruit punch flavor, and combinations thereof. In a preferred embodiment, the formulations contain strawberry flavor.

[00( 55] If the formulations contain a flavoring agent, the formulations preferably contain from about 0,001 to about 1 % flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0.5 % of the flavoring agent.

[00056] The formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration. Preferably, the formulations are liquids administered orally. More preferably, the formulations are simple solutions administered orally.

Formulations Containing Aicoliol

[00057] in another embodiment, the invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 40 % of a cannabinoid, from about 0, 1 to about 25 % of a polyethylene glycol, from about 0.1 to about 40 % of propylene glycol, optionally from about 0.1 to about 50 % of water, and from about 0.1 to about 70 % of alcohol, wherein the formulation has a pH of from about 5 to about 8.

[00Θ58] in a preferred embodiment, the formulations contain from about 1 to about

35 % of a ca mabinoid. In a more preferred embodiment, the formulations contain from about 1 to about 15 %, from about. 5 to about 12 % or from about 7 to about 11 % cannabinoid. Alternatively, the formulations may contain from about 20 to about 35 % or from about 30 to about 35 % cannabinoid.

[00059] in yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidioi, dronabinol (delta-9- tetrahydrocannabinol), delta~8-tetrahydrocannabinol, 11 -hydroxy-tetrahydrocannabinol, 1 1 -hydroxy-delta-9-tetrahydrocannabinol, levonantradol, delta- 1 1 -tetrahydrocannabinol, tetrahydrocannabivarin. amandamide, nabilone, acids, analogs, and synthetic derivatives thereof. In a preferred embodiment, the cannabinoid is cannabidioi.

[00060] in a preferred embodiment, the formulations contain from about 1 to about

35 % of a cannabidioi. In a more preferred embodiment, the formulations contain from about 1 to about 15 %, from about 5 to about 12 % or from about 7 to about 11 % cannabidiol. Alternatively, the formulations may contain from about 20 to about. 35 % or from about 30 to about 35 % cannabidiol.

[00061] In yet another embodiment, the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98 %. in a more preferred embodiment, the cannabidiol is greater than 99 % pure. In an even more preferred embodiment, the cannabidiol is greater than 99.5 % pure. In a most preferred embodiment, the cannabidiol formulation contains less than 0.3 % delta-9- tetrahydrocannabinol.

[00062] in another embodiment, the formulations contain from about 0.001 to about 1 % of an antioxidant. In a preferred embodiment, the formulations contain from about 0.01 to about 1 % antioxidant. In a more preferred embodiment, the formulations contain from about 0.02 to about 0.5 % antioxidant.

[00063] Suitable antioxidants include butylated hydroxyltoluene ("BHT"), butylated hydroxyl anisole ("BHA"), alpha-tocopheroi (Vitamin E), ascorbyl paimitate, ascorbic acid, sodium ascorbate, ethylenediamino tetraacetic acid, cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gailate, sodium sulfate, tert-butylhydroquinone ("TBI-1Q") and combinations thereof, in a preferred embodiment, the formulations contain alpha-toeopherol (Vitamin E), ascorbyl paimitate, or combinations thereof.

[ΘΘ064] In another embodiment, the formulations contain from about I to about

20 % of propylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 15 % or from about 5 to about 10 % propylene glycol.

[00065] In an alternative embodiment, the formulations contain from about 20 to about 50 % of propylene glycol. In a preferred embodiment, the formulations contain from about 30 to about 40 % or from about 35 to about 40 % propylene glycol

[00066] In another embodiment, the formulations contain from about 1 to about

20 % of a polyethylene glycol. In a preferred embodiment, the formulations contain from about 1 to about 10 % or from about 1 to about 5 % polyethylene glycol. [00067] In an alternative embodiment, the formulations contain from about 10 to about 30 % of a polyethylene glycol. In a preferred alternative embodiment, the. formulations contain from about 15 to about 25 % polyethylene glycol

[00068] Suitable polyethylene glycols include low molecular weight polyethylene glycols with an average molecular weight of between 200 and 10,000. One preferred polyethylene glycol that can be used is polyethylene glycol 400.

[00069] In another embodiment, the formulations contain from about 1 to about

20 % of polyethylene glycol 400. in a preferred embodiment, the formulations contain from about 1 to about 10 % or from about 1 to about 5 % polyethylene glycol 400.

[Θ007Θ] In an alternative embodiment, the formulations contain from about 1 to about 5 % of polyethylene glycol 400. In a preferred alternative embodiment, the formulations contain from about 15 to about 25 % polyethylene glycol 400.

[00071] In a further embodiment, the formulations contain water. The formulations can contain 0 % water, if the formulations contain water, they can include from about 1 to about 40 % water, from about 5 to about 40 % water, from about 10 to about 35 % water or from about 25 to about 35 % water.

[00072] In yet another embodiment, the formulations contain from about 1 to about

65 % alcohol. In a preferred embodiment, the formulations contain from about 10 to about 65 %, from about 15 to about 60 %, or from about 30 to 55 % alcohol.

[00073] In an alternative embodiment, the formulations contain from about 1 to about 20 % alcohol. In a preferred alternative embodiment, the formulations contain from about 1 to about 10 % or from about 3 to about 7 % alcohol.

[00074] The H of the formulations may be modified using any pharmaceutically acceptable means. Preferably the pH of the formulations is from about 6 to about 7. In a more preferred embodiment, the pH of the formulations is from about 6.2 to about 6.7.

[00075] The formulations of the present invention may also contain sweeteners, sweetener enhancers, pH modifiers, preservatives, and flavoring agents.

[00076] Suitable sweeteners include, but are not limited to, sucrose, aspartame, saccharin, dextrose, mannitol, xylite], and combinations thereof. [00077] If the formulations contain a sweetener, the formulations preferably contain from about 0,001 to about 1 % sweetener.

[00078] Suitable sweetness enhancers include, but are not limited to, the ammonium salt forms of crude and refined Gl cyrrliizic Acid. Magnasweet^® products (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation) use the ammonium salt forms of crude and refined Glycyrrhizic Acid. Glycyrrhizic Acid is also available as a pure derivative in the sodium and potassium salt forms.

[00079] if the formulations contain a sweetness enhancer, the formulations preferably contain from about 0.001 to about 1 % sweetness enhancer,

[00080] Suitable pH modifiers include, but are not. limited to, hydrochloric acid, ascorbic acid, citric acid, sodium citrate, fun aric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, and combinations thereof.

[00081] Suitable preservatives include, but are not limited to, methyl paraben, propyl paraben, benzyl alcohol, benzoic acid, sodium benzoate, sorbic acid, and combinations thereof.

[00082] Suitable flavoring agents include, but are not limited to, raspberry, peppermint oil, grape flavor, menthol, spearmint oii, citrus oii, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oii, lemon oil, lemon mint flavor, fruit punch flavor, and combinations thereof, in a preferred embodiment, the formulations contain fruit, punch flavor, raspberry flavor, grape flavor, or lemon mint, flavor.

[00083] If the formulations contain a flavoring agent, the formulations preferably contain from about 0.001 to about 1 % flavoring agent. In a more preferred embodiment, the formulations contain from about 0.005 to about 0,5 % of the flavoring agent.

[00084] The formulations are suitable tor oral, buccal, sublingual, inhalation or intravenous/intramuscular administration, Preferably, the formulations are liquids administered orally. More preferably, the formulations are simple solutions administered orally.

Formulations Containing Lipids [00085] in another embodiment, the invention is directed to stable pharmaceutical formulation for oral administration comprising from about 0.1 to about 40 % of a cannabinoid and from about 10 to about 95 % of a lipid.

[00086] in a preferred embodiment, the lipid is selected from the group consisting of sesame oil, olive oil, corn oil, sunflower oil, safflower oil, flaxseed oil, almond oil, peanut oil, walnut oil, cashew oil, castor oil, coconut oil, palm oil, soybean oil, canola oil, vegetable oil, rice bran oil, , fatty acids including caproic acid, eiianthic acid, caprylic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, oleic acid, stearic acid, nonadecylic acid, linoleic acid, araehidic acid and arachidonie acid, medium chain glycerides, decanoy.3 glycerides, octanoyl glycerides, caprylic/capric triglyceride , caprylic/capric/linoleic triglyceride, oleoyl polyoxyl~6 glycerides, linoleoyi polyoxyl-6 glycerides, polygiyceryl- 3 dioleaie, glyceryl monolinoleate, glyceryl nonocaprylate, oleic acid, and a combination thereof, ϊη a more preferred embodiment, the lipid is a medium-chain triglyceride whose fatty acids have an aliphatic tail of from 6 to 12 carbon atoms. In a most preferred embodiment, the lipid is caprylic/capric triglyceride.

[00087] Suitable commercial sources for the lipid include Miglyol^® 812N

(caprylic/capric triglyceride) containing a proprietary mixture of decanoyl and octanoyl glycerides (fatty acid esters) (Miglyol is available from and a registered trademark of Cremer Oieo GmbH & Co.) and Miglyol® 840 (caprylic/capric/linoleic triglyceride) containing a proprietary mixture of propylene glycol dicapryiate/dicaprate and otherwise known as deeanoic acid/octanoic acid/propane- 1 ,2-diol.

[00088] In yet another embodiment, the formulations contain a cannabinoid selected from group consisting of cannabinol, cannabidiol, dronabinol (deita~9~ tetrahydrocannabinol), delta-8-tetrahydrocannabino3_} 1 1 -hydroxy-tetrahydrocannabinol, 1 1 -hydroxy-deIia-9-tetrahyd.iOcannabi.no I , levonantradol, delta- 3 1 -tetrahydrocannabinol, tetrahydrocannabivarin, araandamide, nabiione, acids, analogs, and synthetic derivatives thereof. In a preferred embodiment, the cannabinoid is cannabidiol.

[00089] In yet another embodiment, the formulations contain cannabidiol that is substantially pure and synthetically synthesized which has a purity of greater than 98 %,

33 In a more preferred embodiment, the carmabidioi is greater than 99 % pure. In an even more preferred embodiment, the carmabidioi is greater than 99.5 % pure, in a most preferred embodiment, the cannabidiol formulation contains less than 0.3 % delta-9- tetrahydrocannabinol .

[00090J In a preferred embodiment, the formulations contain from about 1 to about

35 % of a cannabidiol. In a more preferred embodiment, the formulations contain from about 10 to about 32 % cannabidiol. In a most preferred embodiment, the formulations contain about 31.09% cannabidiol.

[00091] In a preferred embodiment, the formulations contain from about 20 to about 90 % of lipids. In a more preferred embodiment, the formulations contain from about 50 to about 90 % lipids. In a most, preferred embodiment, the formulations contain from about 50 to about 74 % lipids.

[00092] In yet another embodiment, the formulations contain alcohol. The formulations can contain 0 % alcohol. If the formulations contain alcohol, they can include from about 0.1 to about 20 % alcohol. In a preferred embodiment, the formulations contain from about 1 to about 15 % alcohol. In a more preferred embodiment, the formulations contain from about 1 to about 10 % alcohol,

[00093] In another embodiment, the formulations contain an antioxidant. The formulations can contain 0 % antioxidant. If the formulations contain antioxidant, they can include from about 0.01 to about 1 % of an antioxidant. In a preferred embodiment, the formulations contain from about 0,02 to about 0.5 % antioxidant,

[00094] Suitable antioxidants include butylated hydroxyltoluene, butylated hydroxyl anisole, aipha-tocopherol (Vitamin E), ascorbyl palmitate, ascorbic acid, sodium ascorbate, ethyienediamino tetraacetic acid, cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, TBHQ, and combinations thereof. In a preferred embodiment, the formulations contain alpha-iocophero! (Vitamin E), ascorbyl palmitate or combinations thereof. [00095] Suitable sweeteners include, but are not limited to, sucrose, aspartame, saccharin, dextrose, mannitol, xylitol, and combinations thereof. In a preferred embodiment the sweetener is saccharin.

[00096] If the formulations contain a sweetener, the formulations preferably contain from about 0.01 to about 2 % sweetener. In a more preferred embodiment, the formulations contain from about 0.01 to about 0.8 % sweetener, in a most preferred embodiment, the formulations contain from about 0.02 to about 0.05 % sweetener.

[00097] Suitable sweetness enhancers include, but are not limited to, the ammonium salt forms of crude and refined Glycyrrhizie Acid, Magnasweet^® products (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation) use the ammonium salt forms of crude and refined Glycyrrhizie Acid, Glycyrrhizie Acid is also available as a pure derivative in the sodium and potassium salt forms.

[00098] If the formulations contain a sweetness enhancer, the formulations preferably contain from about 0.001 to about i % sweetness enhancer.

[00099| Suitable pH modifiers include, but are not limited to, hydrochloric acid, ascorbic acid, citric acid, sodium citrate, fumaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, and combinations thereof.

[000100] Suitable preservatives include, but are not limited to, methyl paraben, propyl paraben, benzyl alcohol, benzoic acid, sodium benzoate, sorbie acid, and combinations thereof,

[000101] Suitable flavoring agents include, but are not limited to, raspberry, peppermint oil, grape flavor, menthol, spearmint oil citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, lemon oil, lemon mint flavor, fruit punch flavor, and combinations thereof. In a preferred embodiment the flavoring agent is strawberry flavor.

[000102] if the formulations contain a flavoring agent, the formulations preferably contain from about 0.01 to about 1 % flavoring agent, in a more preferred embodiment, the formulations contain from about 0.005 to about 0,5 % of the flavoring agent. [000103] The formulations are suitable for oral, buccal, sublingual, inhalation or intravenous/intramuscular administration. Preferably, the formulations are liquids administered orally.

Free, and lipid) and Syntheticaliy Svnthesi¾ed> Subsiantsa!iy Pure. Car ahifiiol

[000104] The formulations of the present invention are especially suitable for treatment of many diseases or disorders or symptoms of diseases and disorders. Further, camiabidiol which is synthetically synthesized and substantially pure will be even more effective and suitable for the treatment of diseases or symptoms of these diseases.

[000105] The formulations of the present invention may be administered to a patient in a fed condition. As used herein a "fed condition" refers to a patient that consumes food prior to administration of a formulation of the present invention and from which the food has not been cleared from the gastrointestinal tract prior to the administration,

[000106] Disease and disorders or symptoms of these disease or disorders that can be treated or prevented by formulations of the present invention include, but are not limited to, Prader-Willi syndrome, obesity, graft versus host disease, gelastic seizures/hypothalamic hamartoma, neonatal seizures, movement disorders including dystonia, central pain syndromes including but not limited to complex regional pain syndrome, phantom limb pain, multiple sclerosis, traumatic brain injury, radiation therapy, acute and chronic graft versus host disease, T-celi autoimmune disorders, colitis, Dravet Syndrome, Lennox Gastaut Syndrome, mycolonic seizures, juvenile mycolonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's Disease, autism, acne, Parkinson's disease, social anxiety disorder, depression, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic injury of heart, ischemic injury of brain, chronic pain syndrome, rheumatoid arthritis, patients encountering adverse emotional stimuli, nausea and addiction disorders related to drugs of abuse such as opioid, heroin, cocaine, amphetamine dependence and including acute and long-term treatment of dependence and relapse associated with drugs of abuse.

[000 J 07] As first explained in US Patent Application No, 62/004,495, Applicant unexpectedly created a new synthetic pathway for creating cannabidiol. This new process eliminated the need to grow cannabis in order to extract camiabidioL Applicant's carmabidiol has a high purity level and is substantially free of Schedule ί drugs, including delta-9-tetrahydrocannabinol .

[000108] Applicant chemically synthesized cannadbidiol by combining p- menthadieno! and olivetol in toluene or dichloromethane or hexane with a p-toluene sulfonic acid catalyst to produce cannabidiol (see diagram below).

p-MenthadienoI Olivetol Camiabidio!

[000109] In an embodiment, the present invention is directed to methods for treating

Prader-Willi syndrome comprising administering the formulations of the present invention to a patient in need thereof,

[000110] In another embodiment, the present invention is directed to methods for treating a Prader-Willi syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000111] In an embodiment, the present invention is directed to methods for treating comprising admirustering the formulations of the present invention to a patient in need thereof.

[000112] in another embodiment, the present invention is directed to methods for treating obesity comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof. [000113] in an embodiment, the present invention is directed to methods for treating graft versus host disease comprising administering the formulations of the present invention to a patient in need thereof.

[000114] In another embodiment, the present invention is directed to methods for treating graft versus host disease comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000115] In an embodiment, the present invention is directed to methods for preventing or treating acute and chronic graft versus host disease comprising administering the formulations of the present invention to a. patient in need thereof

[000116] in another embodiment, the present invention is directed to methods for preventing or treating acute and chronic graft versus host disease comprising administering syntheticaUy synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000117] In an embodiment, the present invention is directed to methods for treating gelastic seizures/hypothaiamie hamartoma comprising administering the formulations of the present invention to a patient in need thereof.

[000118] In another embodiment, the present invention is directed to methods for treating gelastic seizures/hypothaiamie hamartoma comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000119] In an embodiment, the present invention is directed to methods for treating neonatal seizures comprising administering the formulations of the present invention to a patient in need thereof.

[0001201 In another embodiment, the present invention is directed to methods for treating neonatal seizures comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000121] In another embodiment, the present invention is directed to methods for treating movement disorders comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof, preferably the movement disorder is dystonia. [000122] In an embodiment, the present invention is directed to methods for treating movement disorders comprising administering the formulations of the present invention to a patient in need thereof, preferably the movement disorder is dystonia.

[000123] In another embodiment, the present invention is directed to methods for treating central pain syndromes comprising administering synthetically synthesized, substantially pure, carrnahidioi to a patient in need thereof, preferably the central pain syndrome is comple regional pain syndrome,

[000124] In an embodiment, the present invention is directed to methods for treating central pain syndromes comprising administering the formulations of the present invention to a patient in need thereof, preferably the central pain syndrome is comple regional pain syndrome.

[000125] In an embodiment, the present invention is directed to methods for treating phantom limb pain comprising administering the formulations of the present invention to a patient in need thereof.

1000126] in another embodiment, the present invention is directed to methods for treating phantom limb pain comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof.

[000127] in an embodiment, the present invention is directed to methods for providing neuroprotection after stroke comprising administering the formulations of the present invention to a patient in need thereof.

[000128] In another embodiment, the present invention is directed to methods for providing neuroprotection after stroke comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof.

[000129] In an embodiment, the present invention is directed to methods for treating traumatic brain injury comprising administering the formulations of the present invention to a patient in need thereof.

[000130] In another embodiment, the present invention is directed to methods for treating traumatic brain injury comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof. [000131] In an embodiment, the present invention is directed to methods for treating brain injury due to radiation therapy comprising administering the formulations of the present invention to a patient in need thereof.

[000132] In another embodiment, the present invention is directed to methods for treating brain injury due to radiation therapy comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000133] In an embodiment, the present invention is directed to methods for providing enhancement of neural repair following traumatic brain injury, concussion, cerebral infarction, brairx irradiation or encephalomyelitis comprising administering the formulations of the present invention to a patient in need thereof.

[000134] in another embodiment, the present invention is directed to methods for providing enhancement of neural repair following traumatic brain injur)_', concussion, cerebral infarction, brain irradiation or encephalomyelitis comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof. 000135] In an embodiment, the present invention is directed to methods for providing recovery from myocardial infarction comprising administering the formulations of the present invention to a patient in need thereof.

[000136] In another embodiment, the present invention is directed to methods for providing recovery from myocardial infarction comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000137] in an embodiment, the present invention is directed to methods for providing recovery from radiation injury comprising administering the formulations of the present invention to a patient in need thereof preferably radiation injury to lung, bowel, kidney, and heart.

[000138] In another embodiment, the present invention is directed to methods for providing recovery from radiation injury comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof, preferably radiation injury to lung, bowel, kiclney, and heart. [000139] In an embodiment, the present invention is directed to methods for treating a brain tumor comprising administering the formulations of the present invention to a patient in need thereof.

1000140] in another embodiment, the present invention is directed to methods for treating a brain tumor comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof,

[000141] In an embodiment, the present invention is directed to methods for treating

T-cell autoimmune disorders comprising administering the formulations of the present invention to a patient in need thereof. 000142] In another embodiment, the present invention is directed to methods for treating T-cell autoimmune disorders comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000143] in an embodiment, the present invention is directed to methods for treating colitis comprising administering the formulations of the present invention to a patient in need thereof.

[000144] In another embodiment, the present invention is directed to methods for treating colitis comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof,

[000145] In an embodiment, the present invention is directed to methods for treating glioma comprising administering the formulations of the present invention to a patient in need thereof.

[000146] In another embodiment, the present invention is directed to methods for treating glioma comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000147] In an embodiment, the present invention is directed to methods for treating glioblastoma multiforme comprising administering the formulations of the present invention to a patient in need thereof. [000148] In another embodiment., the present invention is directed to methods for treating glioblastoma multiforme comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof.

[000149] In an embodiment, the present invention is directed to methods for treating

Dravet Syndrome comprising administering the formulations of the present invention to a patient in need thereof.

[000150] In another embodiment, the present invention is directed to methods for treating Dravet Syndrome comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof,

[000151] In yet another embodiment, the present invention is directed to methods for treating Lennox Gastaut Syndrome comprising administering the formulations of the present invention to a patient in need thereof.

[000152] In another embodiment, the present invention is directed to methods for treating Lennox Gastaut Syndrome comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof,

[000153] In a further embodiment, the present invention is directed to methods for treating Mycolonic Seizures comprising administering the formulations of the present invention to a patient in need thereof. In a more preferred embodiment, the alcohol-free formulations contain substantially pure eannabidiol.

[000154] in another embodiment, the present invention is directed to methods for treating Mycolonic Seizures comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof.

[000155] In a further embodiment, the present invention is directed to methods for treating Juvenile Mycolonic Epilepsy comprising administering the formulations of the present invention to a patient, in need thereof In a preferred embodiment, the alcohol - free ibrmulations of the present invention are administered to young patients in need of treatment, [000156] In another embodiment, the present invention is directed to methods for treating Juvenile Myoclonic Epilepsy comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000157] In an embodiment, the present invention is directed to methods for treating

Refractory Epilepsy comprising administering the formulations of the present invention to a patient in need thereof, In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment,

[000158] In another embodiment, the present invention is directed to methods for treating Refractory Epilepsy comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000159] in an embodiment, the present invention is directed to methods for treating juvenile spasms comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment,

[ΟΟΟίβθ] in another embodiment, the present invention is directed to methods for treating juvenile spasms comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000161] In an embodiment, the present invention is directed to methods tor treating

West Syndrome comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

[000162] In another embodiment, the present invention is directed to methods for treating West Syndrome comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000163] In an embodiment, the present invention is directed to methods for treating infantile spasms comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment. [000164] In another embodiment, the present invention is directed to methods for treating infantile spasms comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof,

[000165] In a embodiment, the present invention is directed to methods for treating refractory infantile spasms comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

[000166] In another embodiment, the present invention is directed to methods for treating refractory infantile spasms comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof.

[000167] In an embodiment, the present invention is directed to methods for treating tuberous sclerosis complex comprising administering the formulations of the present invention to a patient in need thereof, In a preferred embodiment, the alcohol-free formulations of the present invention are administered to young patients in need of treatment.

[000168] In another embodiment, the present invention is directed to methods for treating tuberous sclerosis complex comprising administering synthetically synthesized, substantially pure, eannabidiol to a patient in need thereof. 000169] In a further embodiment, the present invention is directed to methods for treating neuropathic pain comprising administering the formulations of the present invention to a patient in need thereof, In a further embodiment, the neuropathic pain is caused by neurotoxic chemotherapy agents such as Paclitaxel, Docetaxel, Cisplatin, Oxaliplatin, Carboplatin, Vincristine, Methotrexate, Cytarabine, Fiuorouracil. Ifosfamide, Cyclophosphamide, Procarbazine, etoposide, Carmustine, and Lomustine, In yet another embodiment, the neuropathic pain is caused by Paclitaxel and the patient is receiving Paclitaxel due to a diagnosis of breast, cervical, endometrial and/or ovarian cancer. In a further embodiment, the breast, cervical, endometrial and/or ovarian cancer is platinum- resistant. In another embodiment, the breast, cervical, endometrial and/or ovarian cancer is recurrent. [000170] In another embodiment, the present invention is directed to methods for treating neuropathic pain comprising administering synthetically synthesized, substantially pure, cannabidioi to a patient in need thereof. In a further embodiment, the neuropathic pain is caused by neurotoxic chemotherapy agents such as Paclitaxel, Docetaxel, Cisplatin, Oxaliplatin, Carboplatin, Vincristine. Methotrexate, Cytarabine, Fluorouracil, Ifosfamide, Cyclophosphamide, Procarbazine, etoposide, Camiustine, and Lomustine. In yet another embodiment, the neuropathic pain is caused by Paclitaxel and the patient is receiving Paclitaxel due to a diagnosis of breast, cervical, endometrial and/or ovarian cancer, in a further embodiment, the breast, cervical, endometrial and/or ovarian cancer is platinum-resistant. In another embodiment, the breast, cervical, endometrial and/or ovarian cancer is recurrent.

[0Θ0171] In a further embodiment, the present invention is directed to methods for using cannabidioi as an analgesic comprising administering the formulations of the present invention to a pati ent in need thereof.

[000172] In another embodiment, the present invention is directed to methods for using cannabidioi as an analgesic comprising administering synthetically synthesized, substantially pure, cannabidioi to a patient in need thereof.

[000173] In a further embodiment, the present invention is directed to methods for treating opioid addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol- free formulations of the present invention are administered to the patient in need of treatment.

[000174] In another embodiment, the present invention is directed to methods for treating opioid addiction withdrawal comprising administering synthetically synthesized, substantial !y pure, cannabidioi to a patient in need thereof.

[000175] In yet another embodiment, the present invention is directed to methods for treating cocaine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient In need of treatment. [000176] In another embodiment, the present invention is directed to methods for treating cocaine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000177] in a further embodiment, the present invention is directed to methods for treating heroin addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol- free formulations of the present invention are administered to the patient in need of treatment.

[000178] in another embodiment, the present invention is directed to methods for treating heroin addiction withdrawal comprising administering synthetically synthesized; substantially pure, cannabidiol to a patient in need thereof. 000179] In a further embodiment, the present invention is directed to methods for treating nicotine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol- free formulations of the present invention are administered to the patient in need of treatment.

1000180] in another embodiment, the present invention is directed to methods for treating nicotine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000181] In a further embodiment, the present invention is directed to methods for treating amphetamine addiction withdrawal comprising administering the formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment,

[000182] In another embodiment, the present invention is directed to methods for treating amphetamine addiction withdrawal comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000 J 83] In another embodiment, the present invention is directed to methods for treating drug dependence, wherein treatment is selected from acute and long-term. [000184] In another embodiment, the present invention is directed to methods for treating relapse associated with drug abuse,

[000185] In an embodiment, the present invention is directed to methods for treating acne comprising administering the formulations of the present invention to a patient in need thereof,

[0Θ01 6] In another embodiment, the present invention is directed to methods for treating acne comprising administering synthetical]}' synthesized, substantially pure, ear a idiol to a patient in need thereof.

[000187] In an embodiment, the present invention is directed to methods for treating

Parkinson's disease comprising administering the formulations of the present invention to a patient in need thereof.

[000188] In another embodiment, the present invention is directed to methods for treating Parkinson's disease comprising administering synthetically synthesized, substantially pure, cannabidioi to a patient in need thereof.

[0Θ0Ι89] In an embodiment, the present invention is directed to methods for treating schizophrenia comprising administering the formulations of the present invention to a patient in need thereof.

[000190] In another embodiment, the present invention is directed to methods for treating schizophrenia comprising administering synthetically synthesized, substantially pure, cannabidioi to a patient in need thereof,

[000191] In an embodiment, the present invention is directed to methods for treating social anxiety disorder comprising administering the formulations of the present invention to a patient in need thereof.

[000192] In another embodiment, the present invention is directed to methods for treating social anxiety disorder comprising administering synthetically synthesized, substantially pure, cannabidioi to a patient in need thereof.

[000193] In a further embodiment, the present invention is directed to methods for treating depression comprising administering die formulations of the present invention to a patient in need thereof. [000194] in another embodiment, the present invention is directed to methods for treating depression comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[00ΘΙ95] In a further embodiment, the present invention is directed to methods for treating patients encountering adverse emotional stimuli comprising administering the formulations of the present invention to a patient in need thereof.

[000196] in another embodiment, the present invention is directed to methods for treating patients encountering adverse emotional stimuli comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000197] In an embodiment, the present invention is directed to methods for treating nausea comprising administering the formulations of the present invention to a patient in need thereof.

[000198] In another embodiment, the present invention is directed to methods for treating nausea comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000199] In an embodiment, the present invention is directed to methods for treating multiple sclerosis comprising administering the formulations of the present invention to a patient in need thereof.

[000200] In another embodiment, the present invention is directed to methods for treating multiple sclerosis comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[00020.1] in an embodiment, the invention is directed to methods for treating symptoms of cannabis use disorder comprising administering formulations of the present invention to a patient in need thereof. In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment.

[000202] In another embodiment, the present invention is directed to methods for treating symptoms of cannabis use disorder comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof, [Θ00203] In another embodiment, the invention is directed to methods for treating symptoms of early psychosis comprising administering formulations of the present invention to a patient in need thereof.

[000204] In another embodiment, the present invention is directed to methods for treating symptoms of early psychosis comprising administering synthetically synthesized, substantially pure, camiabidiol to a patient in need thereof.

[000205] in another embodiment, the invention is directed to methods for treating symptoms of Alzheimer's Disease comprising administering formulations of the present invention to a patient in need thereof.

[000206] In another embodiment, the present invention is directed to methods for treating symptoms of Alzheimer's Disease comprising admin stering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[000207] In yet another embodiment, the invention is directed to methods for treating symptoms of post-traumatic stress disorder ("PTSD") comprising administering formulations of the present invention to a patient in need thereof.

[000208] In another embodiment, the present invention is directed to methods tor treating symptoms of post-traumatic stress disorder PTSD comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof

[000209] In an embodiment, the invention is directed to methods for treating symptoms of anxiety comprising administering formulations of the present invention to a patient in need thereof.

[000210] In another embodiment, the present invention is directed to methods for treating anxiety comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

[00 2ii] In a further embodiment, the invention is directed to methods tor treating symptoms of auiism comprising administering formulations of the present invention to a patient in need thereof, In a preferred embodiment, the alcohol-free formulations of the present invention are administered to the patient in need of treatment. [000212] In another embodiment, the present, invention is directed to methods for treating symptoms of autism comprising administering synthetically synthesized, substantially pure, cannabidiol to a patient in need thereof.

Definitions

[000213] As used herein, a "patient" refers to a single patient and not a patient population.

[000214] As used herein, "synthetic" refers to the chemical synthesis of cannabidiol does not refer to cannabidiol that is extracted from cannabis plant material.

[000215] As used herein, "substantially pure" refers to a preparation having ehromatographical purity of cannabidiol of greater than 98 %, preferably greater than 98.5 %. more preferably greater than 99.0 %, and most preferably greater than 99.5 %.

[000216] As used herein, "substantially free of delta-9~teirahydroeanna.binol" refers to a preparation of cannabidiol having less than 0.3 % of delta-9-tetrahydrocarmabinol as determined by HPLC. Preferably, the preparation contains less than 0.25 % of delta~9- tetrahydrocannabinol, more preferably 0.2 %, and most preferably less than 0.1 % of delta-9-ietrahydrocannabinol.

[000217] As used herein, all numerical values relating to amounts, weights, and the like, that are defined as "about" each particuiar value is plus or minus 10 %. For example, the phrase '"about 10 % w/w" is to be understood as "9 % w/w to 1 1 % w/w." Therefore, amounts within 10 % of the claimed value are encompassed by the scope of the claims.

[000218] As used here, "liquid" refers to a flowable, fluid pharmaceutical formulation, This type of formulation is not a powder to solid,

[000219] All weights herein refer to % w/w or percent weight of the total formulation.

[000220] As used herein the term "effective amount" refers to the amount necessary to treat a patient in need thereof.

[000221] As used herein the term "pharmaceutically acceptable" refers to ingredients that are not biologically or otherwise undesirable in an oral dosage form. [000222] As used herein, "qs" means a sufficient quantity of that component to reach a desired volume or concentration.

[000223] The disclosed embodiments are simply exemplary embodiments of the inventive concepts disclosed herein and should not be considered as limiting, unless the claims expressly state otherwise,

[0002241 The following examples are intended to illustrate the present invention and to teach one of ordinary skill in the art how to use the formulations of the invention. They are not intended to be limiting in any way.

[000225] All claims, aspects and embodiments of the invention, and specific examples thereof, are intended to encompass equivalents thereof.

Examples

Ikam 1. Alcohol - ire c fo n-iuk on

[000226] The formulations in Table 1 below were prepared as follows. All the solvents are purged with nitrogen before using in manufacturing. Vitamin E, methyl parahen, propyl paraben were dissolved in propylene glycol. Polyethylene glycol 400 (PEG400) and a flavoring agent were added to the propylene glycol solution and mixed thoroughly. The water phase was prepared by dissolving sucraiose and sodium ascorbate in water. Next, the solutions were combined and pH adjusted using a pH modifier. The cannabinoid was added to the excipient solution and mixed until dissolved,

[000227] Synthetically synthesized, substantially pure, cannabidiol was used as the cannabinoid.

Strawberry flavor was used as the flavoring agent, -free Formulations

Example 2. Stabilitv of .Alcohol-free . Formulations

81 The formulations listed in Table 1 were subjected to stabilitv at 55 °C ±

2 °C, 40 °C ± 2 °C under 75 % ± 5 % relative humidity, and 25 °C ± 2 °C under 60 % ± 5 % relative humidity. Stability of the formulations was analyzed at specified time points by evaluating for their potency (assay value) and impurity levels, Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Tables 2 to 13 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity. nlity Data for Cannabidlo! Oral Solution Formulation # AF1 stored at

°C ± 2 °C

10 ND-Not Detected

BQL-Belovv Quantification Limit, for unknown impurity only

Table 3. Stability Data for Cannabidioi Oral Solution Formulation # AF2 stored at

55 °C ± 2 °C

ND-Not Detected^'

BQL-Below Quantification Limit, for unknown impurity only Table 4. Stability Data for Cannabidlol Oral Solution Formulation # AF3 stored at

55 °C ± 2 °C

ND-Not Detected

BQL-Below Quantification Limit, for unknown impurity only

Table 5. Stability Data for Cannabidiol Oral Solution Formulation # AF4 stored at

°C ± 2 °C

ND-Not Detected

BQL-Below Quantification Limit, for unknown impurity only

Table 6. Stability Data for Cannabidiol Oral Solution Formulation # AFl stored ¾t

ND-Not Detected

BQL-Below Quantification Limit, for unknown impurity only

7. Stability Data for Cannabidiol Oral Solution Formulation # AF2 stored a

40 °C ± 2 °C under 75 % ± 5 % relative humidity

40 °C - Formulation # AF2

Assay (% of initial concentration) % Cis-cannabidioi^"

% Trans-(1R, 6R)-3 '-methyl

cannabidiol

% Unknown Impurity

Total Impurities (% Area)

ND-Not Detected BQL-Below Quantification Limit, for unknown impurity only

Table 8. Stability Data for Casmabidiol Oral Solution Formulation #AF3 stored at

40 °C ± 2 °C under 75% ± 5% relative humidity

ND-Not Detected

Table 9. Stability Data for Cannabidioi Oral Solution Formulation # AF4 stored at

40 °C ± 2 °C under 75 % ± 5 % relative humidity

25 °C ± 2 °C under 60 % ± 5 % relative

ND-Not Detected

BQL-Below Quantification Limit, for unknown impurity only Stability Data for Cannabidio! Oral Solution Formulation # AF2 s 25 °C ± 2 °C under 60 % ± 5 % relative humidity

25 "C - Formulation # AF2 RRT 0 Week 4 Weeks

Assay (% of initial concentration) 100.00 100.22

% Cis-cannabidiol 1.442 0.01% 0.01%

% Trans-(1 R, 6R)-3'-methyI- 0.05% 0.05% cannabidiol 1.848

% Unknown Impurity 0.776 0.07% 0.07%

Total Impurities (% Area) 0.13% 0.13% Table 12. Stability Data for Caimjsbidto! Oral Solution Formulation # AF3 stored at 25 °C ± 2 °C under 60 % ± 5 % relative humidity

Table 13, Stability Data for Cannabidiol Oral S lution Formulation # AF4 stored at

25 °C ± 2 °C under 60 % ± 5 % relative humidity

000229] Control formulation (# API) showed significant increase in levels of total impurities and decrease in the assay value. Adjusting the pH of formulation (# AF2) in the range of from about 6 to about 7 increased the stability of the formulation in comparison to control formulation. This illustrates the critical role that pH plays in carmabinoid formulations⁵ stability. Applicant determined that the pH should be from about 6 to about 7 for optimal stability. Addition of antioxidants along with pH adjustment further increased the stability of the cannabinoid formulation. For example, formulations # AF3 and # AF4, containing antioxidants) and pH modifiers, showed excellent stability for four weeks regardless of temperature and humidity conditions, 000230] The formulations in Tables 14 and 15 below were prepared as follows.

Ail the solvents were purged with nitrogen before using in manufacturing. Vitamin E, ascorbyi palmitaie, methyl paraben, propyl paraben, sucralose were dissolved in ethanoi, propylene glycol, polyethylene glycol 400, glycerol, flavoring agent, and water were added to the solution and mixed thoroughly. Then, if applicable, the pH of the solution was adjusted using a pH modifier. The cannabinoid was added to the excipient solution and mixed until completely dissolved.

[000231] Synthetically synthesized, substantially pure, cannabidiol was used as the cannabinoid, Strawberry flavor was used as the flavoring agent.

Table 14. Formulations with Alcohol

S Wit

Formulation # AIO

Cannabinoid 32 32

Polyethylene glycol 400 18.8 23.8

Propylene Glycol 39 39

Glycerol 5

Ethanol 5 5

Vitamin E (Alpha Tocopherol) 0.05 0.05

Ascorbyl Palmitate 0.1 0.1

Sucralose 0.05 0.05

Methyl Paraben 0.02 0.02

Propyl Paraben 0.02 0.02

Example 4. Stability of I¾tffltdatio with Alcohol

000232] The formulations listed in ^''fable 14 and Table 15 were subjected to stability at 25 °C ± 2 °C under 60% ± 5% relative humidity and 40 °C ± 2 °C under 75 % ± 5 % relative humidity. Stability of the formulations was analyzed at specified time points by evaluating for their potency (assay value) and impurity levels, Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at 228 ran and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Table 16 to 22 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.

Table 16. Stability Data for Cannabidiol Oral Solution Formulation # A5 stored at

°C ± 2 °C under 60 % ± 5 % relative humidity

ND-Νοΐ Detected BQL-Below Quantiilcatior! Limit, for unknown impurity only

>k 17. ty Data for

°C ± 2 °C under 60 % ± 5 % relative humidity

ND-Not Detected

BQL-Beiow Quantification Limit, for unknown impurity only Table 18. Stability Data for Cannabidio! Oral Solution Formulation # A7 stored at

°C ± 2 °C under 60 % ± 5 % relative humidity

BQL-Below Quantification Limit, for unknown impurity only

Table 19. Stability Data for Carniabidiol Oral Solution Formulation # AS stored at

25 °C ± 2 °C *mder 60 % ± 5 % relative humiditv

ND-Not. Detected

BQL-Below Quantification Limit, for unknown impurity only Table 20, Stability Data for Cannabidiol Oral Solution Formulation # A7 stored at 40 °C ± 2 °C under 75 % ± 5 % relative humidity Total impurities (% Area) 0.07 3.18 4.94

ND-Not Detected

BQL-Below Quantification Limit, for unknown impurity only

Table 21. Stability Data for Casmabidiol Oral Solution Formulation # A8 stored at

40 °C ± 2 °C under 75 % ± 5 % relative humiditv

ND-Not Detected

[.-Below Quantification Limit, for unknown impurity only Table 22. Stability Data for Caiinabidlol Oral Solution Formulation # A9 stored at 40 °C ± 2 °C under 75 % ± 5 % relative humidity

Table 23. Stability Data for Caenabidiol Oral Solution Formulation # All) stored at

40 °C ± 2 °C under 75 % ± 5 % relative humidity

ND-Not Detected

[000233] Control formulation (# A5) showed significant increase in levels of total impurities and decrease in the assay value. The addition of antioxidants, Vitamin E and ascorby] palmitate (see # A6) significantly increased the stability of formulation. These results illustrate the critical role of antioxidants in stabilizing cannabinoid foniiulations. Antioxidants Vitamin E and ascorbic acid (or its salt) show excellent synergism as ascorbic acid (or its salt) strongly inhibits the depletion of Vitamin E by regenerating it. Along with the antioxidants, the addition of pH modifiers to adjust the pH to the range of 6 to 7 resulted in exceptionally stable formulations (# A7 and # AS). The stability testing data illustrates that the pH range of from ahout 6 to about 7 is critical. Formulations # A9 and # A10 also showed good stability after four weeks,

00234] The formulations in Table 24 were created by mixing ail the solid and liquid excipients in the lipid. Cannabidiol was then dissolved. Synthetically synthesized, substantially pure, cannabidiol used as the source of the cannabinoid. Strawberry was used as the source of flavoring.

Table 24. Formulations with Li ids

Table 25. Additional Formulations with Lipids

Ethanol l .( 1.0 5.0 10.0

Table 26. Additional Formulations with Lipids

Saccharin 0.025 : 0.025 0,025 ^; 0.025 0.025 0.025 0.025 0.025

Caprylie/Caprie

Triglyceride

(Migi ol® 812N) 68.58 68,575 64.535 64.535 58.585 68.565 63.565 58.565

Migiyol® 840 II; liiiiiii

Jli IJIIII

Olive Oil ill Jilt

EihanoS 1 5 10

E aatfe 6: Stability of :a Foimu ition with. Lip ds

[ 0Θ235] Formulation #LF1 was subjected to stability at 25 °C ± 2 °C under 60 % ±

5 % relative humidity and 40 °C ± 2 °C under 75 % ± 5 % relative humidity. Formulations #LFI 0 and #LF 1 1 were subjected to stability at 55 °C ± 2 "C and 40 °C ± 2 °C under 75 % ± 5 % relative humidity. Formulations #LF8, #LF9 and #LF12-#LF15 were subjected to stability at all 3 storage conditions. The stability of the formulation was analyzed at specified time points by evaluating the potency (assay value) and impurity levels. Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at 228 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 228 nm and expressed as a % area. Amounts of particular impurities are listed in Table 25 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (RRT) is given for each impurity.

Table 26, Three Month Stability Data for Cannahidioi Oral Solution Formulation #LF1 stored at 40 °C ± 2 °C eder 75% ± 5% relative humidity and stored at 25 °C ± 2 °C under 60% ± 5% relative humidity

Table 27. Stability Data for Cannabidioi Oral Solution Formulation #LF8 stored at 55°C ± 2 °C

D-Not Detected

Table 28. Stability Data for Cannabidioi Oral Solution Formulation #LF9 stored at 5S°C ± 2 °C

S3 Concentration)

% Cannabinol 1.395 ND ND ND ND 1 0.01

% Cis-cannabidiol 1.450 0.01 0.01 0.02 0.02 0.02

% Delta 9-THC 1.749 ND ND ND ^' 0.03 0,04

% Trans-(1R, 6R)-3'-methyl-

1.862 0.05 0.06 0.04 0.04 ND cannabidiol

i_. 0.396 ND BQL ] BQL 0.05 0.06

0.455 ND BQL 0.06 I 0.09 0.11

0.480 ND 0.11 0.18 0.32 0.39

0.499 ND 0.07 0.11 0.18 0.23

% Unknown Impurity 0.52.0 ND BQL BQL 0.07 0.08

0.584 ND BQL BQL 0.07 0.09

0.771 0.07 0.07 0.07 0.05 ^"" 0.05

0.796 ND 0.09 0.21 0.40 0.60

0.824 ND 0.05 0.09 0.10 0.11

0.853 ND BQL BQL BQL 0.06

0.920 ND ND BQL BQL 0.05

1.908 ND BQL 0.06 0.13 0.22

Total Impurities (% Area) 0.13 ~ 0^™Ϊ6 ^' 0.84 1.55 2.12

ND-Not Detected

BQL-Below Quantification Limit

Table 29. Stability Data for Camiabidiol Oral Solution Formulation #LF10 stored at

55°C ± 2 °C

ND-Νοΐ Detecte

BQL-Below Quaniificaiion Limit

Table 30, Stability Da a for Camiabidiol Oral Solution Formulation #LF11 stored at 55°C ± 2 °C

ND-Not Detected

BQL- Below Quantification Limit

Table 31. Stability Date for Cannabidiol Oral Solution Formulation #LFJ2 stored at 55°C ± 2 °C

% Unknown Impurity 0.584 i; ND BQL, BQL _ ^{0 17} 0.10

0.771 0X17 0.07 0.07 ~^~0.06 0.07

0,796 ND 0.06 0.14 0.21 0.34

0.824 ND ND : 0.05 BQL 0.06 ^■

Total Impurities (% Area) 0.13 0.27 0.42 0.75 1.12

ND-Not Detected

BQL-Below Quantification Limit

Table 32. Stability Date for Cans labidiol Oral Solution Formulation #LF13

°C ± 2 °C

ND-Noi Detected

Table 33. Stability Data for Cannabidiol Oral Solution Formulation #LF14

stored at 55°C ± 2 °C

ND-Not Detected

Table 34. Stability Data for Cannabidiol Oral Solution Formulation #LF15

stored at 55°C ± 2 °C

% Total Impurities (% Area) j 0.12 j 0.12 j 013 0,14 0 14

Table 35. Stability Data for Cannabidiol Oral Solution Fo mulation #LF8 stored at 40°C ± 2 °C under 75 % ± 5 % relative humi ity

ND-Not Detected

BQL-Below Quantification Limit

Table 36. Stability Data for Cannabidiol Oral Solution Formulation #LF9 stored at 40°C ± 2 °C under 75 % ± 5 % relative humidit

ND-Not Detected

BQL-Below Quantificat on Limit

Table 37. Stability Data for Cioisiabidioi Oral Solution Formulation #LF10

°C ± 2 oC under 75 % ± 5 % relative humidity

ND-Not Detected

BQL-Below Quantification Limit

Table 38. Stability Data for Cannabidioi Oral Solution Formulation #LF11 stored at 40°C ± 2 °C under 75 % ± 5 % relative humidity

ND-Not Detected Table 39, Stability Date for Casmabidiol Oral Solution Formulation #LF12 stored at 40°C ± 2 °C under 75 % ± 5 % relative humidity

ND-Νοΐ Detected

Table 40. Stability Date for Cannabidiol Oral Solution Formislaiion #LF13 stored at 40°C ± 2 °C under 75 % ± 5 % relative humidity

ND-Not Detected

Table 41. Stability Data for Cannabidiol Oral Solution Formulation #LF14 stored at 40°C ± 2 °C under 75 % ± 5 % relative humidi

ND-Not Detected Table 42. Stability Data for Cannabidiol Os al Solutio n Formal ation #LI stored at 40°C ^ : 2 °C under 75 % ± 5 % rela tive hum! dity

ND-Not Detected

Table 43. Stability Data for Cannabidiol Oral Solution Formulation #LF8 stored at 25°C ± 2 "C under 60 % ± 5 % relative humidity

ND-Not Detected

BQL-Below Quantification Limit

Table 44. Stability Data for Cannabidiol Oral Solution Formulation #LF9

°C ± 2 °C under 60 % ± 5 % relative humidity

Total Impur i lies ( % Area)

Table 45, Stability Data for Cannabidioi Oral Solution Formulation #LF12 stored at 25°C ± 2 °C under 60 % ± 5 % relative humidity

46. Stability Data for Cannabidioi Oral Solution Formulation stored at 25°C ± 2 °C under 60 % ± 5 % relative humidity

Table 47. Stability Data for CanEabidiol Oral Solution Form

stored at 2S°C ± 2 °C under 60 % ± 5 % relative humid

Table 48, Stability Data for Caxmabidiol Oral Solution Form #LF15

°C ± 2 °C under 60 % ± 5 % relative bin:

[Θ00236] As seen in Table 25 above, formulation # LF1 with sesame oil showed good stability after 3 months at both storage conditions 25 °C ± 2 °C/60 % ± 5 % relative humidity and 40 °C ± 2 °C/75 % ± 5 % relative humidity. Also, formulation #LF8 with olive oil showed good stability after four weeks at storage conditions 55°C ± 2 °C, after three months at 25 °C ± 2 °C/60 % ÷ 5 % relative humidity and 40 °C ± 2. °C/75 % ± 5 % relative humidity.

[000237] Formulations #LF9-#LF 15 each contain capyrlic/eapric triglyceride and one of alpha-tocopherol (Vitamin E), ascorbyl palmitate, or a combination thereof as an antioxidant. Formulations #LF13-#LF15 each additionally contain ethanol. Each of formulations #LF9-#LF15 showed good stability after four weeks at storage conditions 55°C ± 2 °C, 40 °C ± 2 °C/75 % ± 5 % relative humidity and 25 °C ± 2 °C/60 % ± 5 % relative humidity. #LF9-#LF12 demonstrate the ability of alpha-tocopherol (Vitamin E) to surprisingly achieve less than 0.5% total impurities after four weeks at 40 °C ± 2 °C/75 % ± 5 % relative humidity. #LF13-#LF15 demonstrate the ability of ascorbyl palmitate to surprisingly achieve less than 0.2% total impurities after four weeks at all 3 storage conditions in formulations containing from 1 % to 5% ethanol. #LF14 demonstrates that the addition of alpha tocopherol (Vitamin E) does not improve the surprising stability from the use of ascorbyl palmitate.

Example 7. FaclitaKei lpdiic d Neuropathic Fain Stody

[000238] Paclitaxel is an antineoplastic agent that has activity against several types of cancer including ovary, breast, lung and the head and neck. Paclitaxel works by promoting microtubule assembly which results in neuropathy as a toxic side effect. Peripheral sensory neuropathy is the .most commonly reported neurotoxic side effect of paclitaxel and it limits treatment with high and cumulative doses of paclitaxel when given alone or in combination with other neurotoxic antineoplastic agents such as eisplatin. Currently there is not a highly effective treatment for this type of pain. Therefore, there is a need for a highly effective treatment to relieve the symptoms of paclitaxel induced neuropathy,

[000239] A mouse study was conducted in order to determine the effects of cannabidiol, delta-9-tetraliydrocannabinol, and cannabidiol plus delta-9- tetrahydrocannabinoi combinations to alleviate neuropathic pain caused by chemotherapy-induced peripheral neuropathy. The cannadidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than 98 %,

[000240] A detailed explanation of Figure 1 is as follows. The Y-axes represent the threshold sensitivity to mechanical stimulation, expressed as a percent of baseline sensitivity. The X-axes represent the dose of drug in milligrams per kilogram ("mg/kg") administered intraperiioneally ("IP".) Whereas the doited lines represent withdrawal threshold level to mechanical stimulation of saline controls, the dashed lines represent paclitaxel-treated animals. The points along the dashed line indicate neuropathic pain while points along the dotted line represent protection from neuropathic pain. The data shown are mean +SEM sensitivity measured on Day 21 post treatment. * p< 0,05 from saline control as determined by one-way ANOVA.

[000241] Specific doses of agents producing similar overt behavioral effects when added to together should produce the additive effect level.

Examples:

1) If 1.25 mg/kg cannabidiol produces 100 % alleviation of pain effect and 1.25

mg/kg delta-9~tetrahydrocannabinol produces 0 % effect, then those doses added together should be fully effective (as should the 2.5 mg/kg cannabidiol + 2.5 mg/kg delta~9-tetrahydrocannabinoi). 2) If 0,625 mg/kg cannabidiol and 0.625 deka-9 etrahydrocannabinol produce 0% effect, then those doses in combination should be ineffective.

[000242] Applicant found (as illustrated in Fig. 1 ) that cannabidiol when administered alone provided the most effective level of alleviating chemotherapy-induced neuropathic pain compared to de!ta~9~ietrahydrocamiabmoi. The presence of delta-9- tetrahydrocannabinol depending on its concentration can inhibit the ability of cannabidiol to alleviate neuropathic pain. The ability of delta-9-tetrahydrocannabinol to block the pain alleviating activity of cannabidiol is also dependent, of the concentration of cannabidiol. This test illustrates that a substantially pure cannabidiol formulation is highly desirable,

Example ¾ . Ad ;itoh¾I Facsitaxei Induced Hewopt e Pain Study Methods

[000243] Paclitaxel was administered on days I , 3, 5, and 7 following baseline mechanical sensitivity, and cam abinoids were administered 15 minutes prior to each paclitaxel injection. Mechanical sensitivity was then reassessed on days 9, 14, and 21. For mechanical sensitivity testing, mice are placed on a wire mesh surface inside individual clear Plexiglas chambers, and the plantar surface of their hindpaw is touched with increasing thicknesses of Von Frey filaments (0.16^■■■· 2.0 grams of force) until they withdraw their paw from the stimulation. Von Frey hairs are a series of fine, calibrated filaments that are pressed against the plantar surface of the mouse into a bent "C" shape for 6 seconds. For each treatment group the final sample size was 8 animals. Two-way ANOVA were used to determine significant effects of CBD and THC treatment.

[000244] Single agent dose effect curves are shown as percent level of mechanical sensitivity at baseline to normalize data. Dose equivalence analysis was used to determine significant synergistic effects of CBD+TFIC compared with predicted additive values derived from single agent dose response curves. To obtain predicted and observed effect levels, data were transformed into percent maximal possible effect (MPE) of the cannabinoid to reverse paclitaxel -induced mechanical sensitivity, To determine this value for each animal, the mean sensitivity score of the paclitaxei control group on given test day is set at zero and the animal's baseline score prior to treatment is set at 100. For example, if an animal has a mechanical sensitivity score of 1.0 at baseline and a score of 0.75 on day 9, and the paclitaxel group shows an average score of 0,5 on day 9, then the animal's percent MPE score is 50%, A %MPE score of 0% would indicate that the animal was at least as sensitive as the paclitaxel control group. A %MPE score of 100% would indicate that the animal was as sensitive or less sensitive on test day as it was at baseline. This transformation of the data is necessary to determine effective dose levels (ED50s, ED25s, etc).

Results

[000245] Pretreatment with CBD or THC significantly attenuated paclitaxel- induced mechanical sensitivity, P<0.0001 for each agent. See Figure 2. CBD produced this effect with higher potency, in that the minimal effective dose for CBD was 1.25 mg/kg IP, while the minimal effective dose for THC was 2.5 mg/kg IP. Two-way ANOVA also revealed a significant difference between the CBD and THC: dose response curves, with the 1 ,25 mg kg dose of CBD producing a significantly higher % baseline score as compared to 1.25 mg/kg dose of THC. Both drugs appeared to be efficacious.

[000246] Across a wider range of doses, it becomes apparent that both CBD and THC do not produce monotonic dose effects but instead follow an inverted-U or N shaped function. For both CBD and THC at each time point, the curve turns over at between 5,0 and 10 mg/kg, but the treatments regain efficacy at higher doses. See Figure 3, top center and middle center panels. In the combination groups, the data appear more U-shaped, although it is unclear whether the rise would again emerge with larger dose combinations. See Figure 3, bottom middle panel.

[000247] Dose equivalence analysis was used to predict the combined effects of CBD and THC based on their effects alone on the ascending limbs of their dose response curves. The individual dose effect equations are £~78.47i?²'⁵/D²"H0.497 for CBD, and £'=80£⁾ /D³+3.44 for THC- In dose equivalence analysis, for each CBD dose, an effect- equivalent dose of THC is identified. This dose is added to the actual THC dose in each combination so that the sum is the effective dose of the predicted combination. For example, to predict the additive effect of 0,31 mg/kg CBD and 0,31 mg/kg THC, a dose of THC is identified that is equi-effective to 0.31 mg/kg CBD using the determined dose effect equation for CBD. CBD 0.31 mg/kg produces a %MPE of 8,3%. From this, the dose of THC to produce a %MPE of 8.3 is calculated using the determined dose effect equation for THC. The dose of THC required to achieve a. %MPE is 0.7 mg/kg, and this represents a dose thai is equi-effective to 0.31 mg/kg CBD. The 0,7 mg/kg is added to the 0.31 mg/kg to give 1.01 mg/kg THC, whose effect level will equal the predicted effect level of 0,31 mg/kg CBD + 0.31 mg/kg THC. This predicted effect level is determined to be 13.68 %MPE, When the actual combination experiment was conducted, 0,31 mg/kg CBD + 0,31 mg/kg THC (labeled on the graph as 0.625 mg/kg combination), was actually the ED78 (78% maximum possible effect; Figure 2 bottom panel). Modified t- test statistics are applied and it was determined that the predicted combination dose response curve was statistically significantly different from the observed dose response curve, demonstrating a synergistic effect of CBD+THC combinations. See Figure 4.

Methods

[000248] A study was designed to test the efficacy of CBD+THC combinations outside of the 1 : 1 dose ratio. Six additional combinations were tested: 4: 1, 3:1 , 2: 1, 1 :2, 1 :3, and 1 :4. Four doses of each treatment combination were tested in groups of mice treated with paclitaxel. For each treatment group the final sample size was 8 animals.

Results

[000249] The 4: 1 combination of CBD to THC produced a similar effect to CBD alone, while 2: 1 and 3: 1 ratios of CBD to THC were more potent than CBD alone. See Figure 5. Two-way ANOVA revealed an overall effect of treatment and of dose (p<0.05) but no significant interaction. Combinations higher in THC than in CBD produced an effect similar to THC alone, with a significant effect of dose (p<0.05) but no main effect of treatment and no significant interaction.

Methods

[000250] A study was designed to test the efficacy of CBD in preventing oxaliplatin- or vincristine- induced peripheral neuropathy. Two doses of CBD and vehicle were tested against each of these first line chemotherapeutic agents. Oxaliplatin was administered once at a dose of 6 trig/kg. CBD was administered 15 minutes prior to die single oxaliplatin injection. Vincristine was administered once daily for 7 days at a dose of 0.1 mg/kg. CBD was administered 15 minutes prior to each vincristine injection. For each treatment group the final sample size was 8 animals.

Results 000251] Pretreatment with CBD attenuated oxaliplatin but not vincristine-induced mechanical sensitivity. See Figure 6. Two-way ANOVA for oxaliplatin revealed a signiiicant effect of time and a significant effect of treatment (p<0,05) and no significant interaction. Two-way ANOVA for vincristine revealed a significant effect of time (p<0.05), but no main effect of treatment and no interaction.

Ex:¾mpi¾ 1.1 , Antic-anvufeaat Stu y 000252] This study was conducted as follows according to standard models for anticonvulsant screening including the maximal electroshock test ("MES"), the minimal clonic seizure ("6 Hz") test and evaluations of toxicity ("TQX"). The data was recorded as number of animals protected (N) out of the number of animals tested (F), see Tables 26 to 29 below. The test was repeated one time. The cannabidiol administered to the mice and rats was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than 98 %. The cannabidiol was dissolved in 0.5% methyleellu!ose or a 1 : 1 : 18 ratio of ethanohpolyethoxylated castor oikphosphate buffered saline ("PBS").

[000253] The maximal electroshock test is a model for generalized tonic-dome seizures and provides an indication of a compound's ability to prevent seizure spread when ail neuronal circuits in the brain are maximally active. These seizures are highly reproducible and are electrophysiological!}' consistent with human seizures. For all tests based on maximal electroshock convulsions. 60Hz of alternating current (50 niA in mice, 150 in rats) was delivered for 0.2s by corneal electrodes which were primed with an electrolyte solution containing an anesthetic agent (0.5% tetracaine HQ), The mice were tested at various intervals following doses of 10, 30 and 100 mg/kg of cannabidiol given by intraperitoneal injection of a volume of 0.01 mL/g. An animal was considered "protected" from maximal electroshock-induced seizures upon abolition of the hind limb tonic extensor component of the seizure. [000254] The minimal motor impairment test was used to determine the compounds' undesirable side effects or toxicity, During this test, the animals were monitored for overt signs of impaired neurological or muscular function. The rotorod procedure was used to disclose minimal muscular or neurological impairment. When a control mouse is placed on a rod that rotates at a speed of 6 rpm, the animal can maintain its equilibrium for long periods of time. The animal was considered toxic if it fell off this rotating rod three times during a 60 second period. In addition to minimal motor impairment, the animals may have exhibited a circular or zigzag gait, abnormal body posture and spread of the legs, tremors, hyperactivity, lack of exploratory behavior, somnolence, stupor, catalepsy, loss of placing response and changes in muscle tone.

|000255J The third test was the minimal clonic seizure (6Hz) test. Like the maximal electroshock test, the minimal clonic seizure (6Hz) test is used to assess a compound's efficacy against electrically induced seizures but uses a lower frequency (6Hz) and longer duration of stimulation (3s), Cannabidiol was pre-administered to mice via intraperitoneal injection. At varying times, individual mice (four per time point) were challenged with sufficient current delivered through corneal electrodes to elicit a psychomotor seizure in 97 % of animals (32 mA for 3 s). Untreated mice will display seizures characterized by a minima] clonic phase followed by stereotyped, automatistic behaviors described originally as being similar to the aura of human patients with partial seizures. Animals not displaying this behavior are considered protected.

Table 49. Anticonvulsant Screening, Mice, Methyicelluiose

Table SO. Anticonvulsant Screening, Mice, Ethano Polyethoxyiated castor oi!:PBS

Table 5L Anticonvulsant Screeni , Rats, Meihykei! lose

Table 52, Anikottvu!saai Sc eening, Rats, EthanohPolyethoxylated castor oi!;PBS

[000256] As seen in Tables 49 to 52 above, Applicant found that cannabidiol protected the mice and rats from epilepsy.

[000257] This study was conducted in order to determine the ability of synthetically-syntheisized, substantially pure cannabidiol to block a psychomotor seizure induced by long-duration frequency (6 Hz) stimulation. This is a study model for therapy-resistant partial seizures. |000258j Adult male CF1 mice (weighing 18 to 25 g) were pretreated intraperitoneally with the cannabidiol at a dose of 100 mg kg. The cannabidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than 98 %. The cannabidiol was dissolved in 0.5% methylcellulose or a 1 : 1 : 18 ratio of ethanokpoiyethoxylated castor oihPBS.

[000259] Each treatment group (n = 4 mice/group) was examined for anticonvulsive effects at one of live time points (1 /4, 1/2, 1 , 2, and 4 hours) following treatment with cannabidiol. Following pretreatment, each mouse received a drop of 0,5 % tetracaine hydrochloride applied to each eye. The mouse was then challenged with the low- frequency (6 Hz) stimulation for 3 seconds delivered through corneal electrodes. The low-frequency, long-duration stimuli was initial ly delivered at 32 mA intensity. Animals were manually restrained and released immediately following the stimulations and observed for seizure activity. If the test compound was effective in the 32 mA screen, an additional assay wherein the stimulation current is increased to 44 mA is employed using the same protocol as described above. Additionally, a dose response curve can be generated at the time of peak effect (TPE) at the specific stimulation intensity,

[000260] Typically, the 6 Hz stimulation results in a seizure characterized by a minimal clonic phase that is followed by stereotyped, automatistic behaviors, including twitching of the vibrissae, and Straub-tail. Animals not displaying such behaviors were considered protected. Data was analyzed by Mann-Whitney U test, with p<0.05 determined to be statistically significant.

[000261] For each time group, the results are expressed as the total number of animals protected out of the number of animals tested over time (i.e., 2/4 represents 2 out of 4 mice tested were protected).

Tabie 53, ED50 Biolo ical Response, Methylcellulose

ΡΓΗΖΗ 190 f 778

Table 54. Time to Peak Effect, Methykel!wlosc

! Time (Honrs) 0.25 L 0.5 I 1 ; 2 [ 4

i Test Dose N/F N/F N/F N/F ! N/F N/F N/F

! 6 Hz 300 1/8 6/8 0/8 0/8 i! 0/8 0/8 0/8 j. 6 Hz 500 1 1/8 078 0/8 0/8 i 0/8 0/8 2/8

Table 55, ED50 Biological Respo se, EifaimolsPolyethoxylate castor oikPBS

Table 56. Tkrae to Peak Effect, Ethanol:PolyethoxyIated castor oikPBS

[000262] As seen in Tables 53 to 56, cannabidiol in both solvents showed comparable median effective doses that inhibited seizures in 50 % of animals (ED50s) in the 100 mg/kg range. While cannabidiol dissolved in the methylcellulose solvent had an ED50 of 103.75 mg/kg (95 % Confidence Interval of 53.89 mg/kg to 163.84 mg/kg), it showed an ED50 of 121.52 mg/kg when dissolved in the 1 : 1 : 18 ethanohpolyethoxylated castor oikPBS solvent (95 % Confidence Interval of 87.83 mg/kg to 152.96 mg/kg). Based on the toxicity data for the cannabidiol in the methylcellulose solvent, the median toxicity dose where toxicity is observed in 50 % of animals ("TD50") was determined to exceed 500 mg kg at 0.5 hours post administration. Diarrhea at 24 hours and 1 death was reported at 24 hours at 500 mg/kg. the highest dose tested.

[000263] The TD50 was determined to be 262.37 mg/kg (95 % Confidence Interval of 232.64 to 301.78) with eannabidiol dissolved in the 1 : 1 : 18 ethanohpoiyethoxylated castor oihPBS solvent. Death was reported at 24 hours at 300 mg kg and at 6 and 24 hours for 500 mg/kg with the with the 1 : 1 : 18 ethanohpoiyethoxylated castor oihPBS solvent.

[000264] These results further illustrate that eannabidiol is likely to be effective in humans for the treatment of epilepsy and other conditions. Further, synthetically synthesized eannabidiol will likely be less toxic than eannabidiol that is derived from plants and not substantially pure.

Example 13. Maximal Electroshock Seizure and Subcutaneous Metrazo i

[000265] The maximal electroshock seizure ("MES") arid subcutaneous Metrazoi ("sc Met") tests have been the two most widely employed preclinical seizure models for the early identification and high through-put screening of investigational anti-seizure drugs. These tests have been extremely effective in identifying new anti-seizure drugs that may be useful for the treatment of human generalized tonic-dome seizures and generalized myoclonic seizures. The MES test provides an indication of CBD's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active. The s.c. Met test detects the ability of CBD to raise the chemoconvulsant- induced seizure threshold of an animal and, thus, protect it from exhibiting a clonic, forebrain seizure.

[000266] For the MES test, 60 Hz of alternating current is delivered by corneal electrodes for 0.2 seconds. Supra-maximal seizures are elicited with a current intensity five times that necessary to evoke a threshold tonic extension seizure, i.e., 50 mA in mice and 150 mA in rats. A drop of anesthetic solution, 0,5 % tetracaine hydrochloride, is placed on the eyes of each animal just before the corneal electrodes are applied to the eyes to elicit electrical stimulation. The animals are restrained by- hand and released immediately following stimulation to allow observation of the entire seizure. Inhibition of the hind leg tonic extensor component is taken as the endpoini for the VIES test.

[000267] A dose of Metrazol (85 mg/kg in mice) will induce convulsions in 97 % of mice (CD97). The CD97 dose of Metrazol is injected into a loose fold of skin in the midline of the neck. The CD97 doses for Metrazol are confirmed annually in mice. It is administered to mice at a volume of 0.01 ml/g body weight. The animals are then placed in isolation cages to minimize stress and continuously monitored for the next 30 min for the presence or absence of a seizure. An episode of clonic spasms, approximately 3 to 5 seconds, of the fore and/or hind limbs, jaws, or vibrissae is taken as the endpoini Animals not displaying fore and/or hind limb clonus, jaw chomping, or vibrissae twitching are considered protected.

[000268] All quantitative in vivo antiseizure/behaviorai impairment studies are typically conducted at the previously determined TPE. Groups of at least 8 mice were tested with various doses of cannabidiol until at least two points are established between the limits of 100 % protection or minimal toxicity and 0 % protection or minimal toxicity. The dose of drug required to produce the desired endpoini in 50 % of animals (BD50 or TD50) in each test, the 95% confidence interval, the slope of the regression line, and the standard error of the mean (S.E.M.) of the slope is then calculated by probit analysis.

[000269] The cannabidiol administered to the mice was substantially pure, synthetically synthesized, cannabidiol which had a purity greater than 98 %. The cannabidiol was dissolved in 0,5% methylcellulose or a 1 :1 : 18 ratio of ethanohpolyethoxylated castor oikPBS. The maximal electric shock (MES) and subsucanteous Metrazol ("sc MET') are the most widely used preclinical seizure models for the early identification and screening of new antiepileptic drugs.

Tabic 57. ED50 Biological Response, Meihyicelluiose

/J

Table 58. T ime to P eak Effect, Meihylce

Time (Honrs) 0.25 [ 0.5 1 ί 2 4 !

Test Dose N/F N/F N/F N F N F j

MES Γ 300 0/4 j 1/4 1/4^' 4/8 j 2/4 ]

Sc MET I 200 0/4 0/4 2/8 3/8

TOX ! 300 0/4 0/4 0/4 0/4 0/4 j

Table 59. ED50 Biological Response, EthanokPoIyethoxykied castor

Table 60. Time to Peak Effect, Et ajioi:PoIyet oxykted castor oifcPBS

[000270] The ED50 in the MES model for cannabidiol dissolved in the methylcellulo.se solvent could not be calculated due to a U shaped dose response (1/4 protected at 0.5 hr, 1/4 at I hr, 4/8 at 2hr and 2/4 at 4hr). However, the ED50 for cannabidiol dissolved in the 1 : 1 :1 8 ethanol:polyethoxlated castor oil:PBS solvent is 92.21 mg/kg (95 % Confidence Interval of 78.4 mg/kg to 104.63 mg kg).

[000271] For the MET model, the ED50 was 241.03 mg/kg (95% Confidence interval of 182.23 to 31 1.87) for cannabidiol dissolved in the methylcellulose solvent and 198.51 mg/kg (95 % Confidence Interval of 167.76 mg/kg to 232.58 rng/kg) for cannabidiol dissolved in the 1 : 1 : 18 ethanokpolyethoxlated castor oikPBS solvent. Based on the toxicity data for cannabidiol dissolved in the methylcellulose solvent the TD50 was determined to exceed 500 mg/kg, the highest dose tested.

[000272] Myoclonic jerks were reported in at 1 hour with 200 mg/kg dose and at 2 hours with 360 mg/kg dose. The TD50 was determined to be 266.76 mg/kg (95 % Confidence Interval of 222.28 mg/kg to 317.42 mg/kg) with the cannabidiol dissolved in the 1 :1 : 18 ethanokpolyethoxlated castor olkPBS solvent.

[000273] These results further illustrate that cannabidiol is likely to be effective in humans for the treatment of epilepsy and other conditions. Further, synthetically synthesized cannabidiol will likely be less toxic than cannabidiol that is derived from plants and not. substantially pure.

Example 14, Gliobla^ a^' ultiforme Study

[000274] A study was conducted in order to determine the extent to which systemic administration of cannabidiol or cannabidiol plus delta-9-tetrahydroeannabinol (cannabidiof/delta-9-tetrahydrocaimabinol 1 : 1) can inhibit, glioblastoma multiforme progression and enhance the activity of temozoiomide, a chemotherapy drug, in an orthotopic mouse model of glioblastoma multiforme utilizing U87 ceils. It was previously suggested that the combination of cannabidiol plus delta-9- tetrabydrocannabinoi is the most effective treatment for targeting tumors derived from U87 serum-derived glioblastoma multiforme cells.

[000275] The study was conducted as follows. Human U87 luciferase labeled cells were grown in Rosweli Park Memorial Institute media with 10 % fetal bovine serum and then harvested from dishes while in their exponential growth phase in culture with 0.1 % trypsin/ethylenediaminetetraacetic acid and washed twice with serum-free Rosweli Park Memorial Institute media. For the intracranial model, tumors were generated in female ath mic nu/nu mice by the intracranial injection of 0.3x1 G^& U87 cells in 4μ1 of Roswell Park Memorial Institute media. Using this model, you can assess drug efficacy (in vivo imaging) as well as survival in the same group of animals. Survival studies were carried out in accordance with the National Institutes of Health's guidelines involving experimental neoplasia and our approved Institutional Animal Care and Use Committees protocol. Animals in all groups are removed from the study when they demonstrate any single sign indicative of significant tumor burden development, including hunched back, sustained decreased general activity, or a significant decrease in weight, in limited cases where tumors were able to escape the intracranial space, the mice were euthanized when the external tumors measured greater than 5mm as assessed by callipers. Additionally, mice with tumors measuring >500xl0⁶ radiance where removed from the study even if symptoms were not observed to assure spontaneous deaths related to seizures did not occur do to the existence of the large intracranial tumor.

[0002761 The cannabinoids were dissolved in a mixture of 3 % efhanol, 3 % surfactant and 94 % saline, and ternozolomide was dissolved in 30 % dimethyl sulfoxide and 70 % saline, Cannabidioi that was synthetically synthesized and substantially pure was used in this study, The treatments were initiated 9 days after the injection of the tumor cells. Mice were imaged the morning before the first injection to determine initial tumor size and then groups were organized to have equal distribution of tumor size before the initiation of the first injection. Mice were treated once a day for five days with ternozolomide. Mice were treated once a day, 5 days a week (Monday through Friday), with the cannabinoids until the completion of the study, except for the first week of the study where mice were injected over the weekend. All mice were administered the treatments via intraperitoneal injection. There were 12 mice per group, for a total of 72 mice. The treatment rates were as follows: cannabidioi ( 15 mg/kg); cannahidiol/deita-9- tetrahydrocannabinol (1 : 1, together @ 15mg/kg); and ternozolomide (2 mg/kg intraperitoneal injection.

[000277] Significant differences were determined using a one-way A OVA. Bonferroni -Dunn post-hoc analyses were conducted when appropriate. Survival between groups was compared using a long-rank Mantel-Cox test. P values <0,05 defined statistical significance.

[0002781 A detailed explanation of Figure 7 is as follows. The X-axis represents the number of days after treatment and the Y -axis represents the survival rates.

[Θ0Θ279] As seen in Figure 7, while 15 mg/kg of cannabidiol alone or cannabidiol/delta~9 etrahydrocannabinoi (1 : 1 ) did not inhibit glioblastoma multiforme progression, it enhanced the antituraor activity of suboptimai doses of temozolomide leading to a significant increase in survival. Further, the substantially pure, synthetically synthesized, cannabidiol produced full regression of 20 % of tumors. This effect was not observed following the 1 : 1 cannabidiol:delta-9-tetraliydrocannabinol treatments. It was unexpected that substantiaily pure, synthetically synthesized, cannabidiol would have these effects because previously it was thought, that a 1 : 1 ratio of cannabidiol (that was extracted from cannabis and not substantially pure):delta-9-tetrahydrocannabinol would produce better effects than cannabidiol alone. However, this study again illustrates the superiority of Applicant's substantiaily pure, synthetically synthesized, cannabidiol.

[0 )02801

Example 1 , Additional Glioblastoma M l!llmffl?g Audy

[000281] Human U251 lueiferase labeled cells were grown in Roswell Park Memorial institute media with 10% fetal bovine serum and then harvested from dishes while in their exponential growth phase in culture with 0,1% trypsin,'' ethylenediaminetetraacetic acid, and washed twice with serum-free Roswell Park Memorial Institute media. For the intracranial model, tumors were generated in female athymic nu/nu mice by the intracranial injection of 0.3x1 Q⁶ U251 cells in 4μ1 of Roswell Park Memorial Institute media. Using this model, you can assess drug efficacy (in vivo imaging) as well as survival in the same group of animals. Survival studies were carried out in accordance with the National Institutes of Health's guidelines involving experimental neoplasia and our approved Institutional Animal Care and Use Committees protocol. Animals in all groups are removed from the study when they demonstrate any single sign indicative of significant tumor burden development, including hunched back, sustained decreased general activity, or a significant decrease in weight. In limited eases where tumors were able to escape the intracranial space, the mice were euthanized when the external tumors measured greater than 5mm as assessed by calipers. Additionally, mice with tumors measuring >500xl0⁶ radiance where removed from the study even if symptoms were not observed to assure spontaneous deaths related to seizures did not occur due to the existence of the large intracranial tumor. There were 12 mice per group, for a total of 72 mice. The treatment rates were as follows: eannabidiol (15 mg kg); temozoiornide (1 .5 mg/kg intraperitoneal injection; and cannabidiol/temozolomide (10: 1 , together at 16.5 mg/kg.)

[000282] For drug treatment studies, cannabinoids were dissolved in a mixture of 2.5 % ethanoi, 2.5 % Tween^® 80 and 95% saline, and temozoiornide was dissolved in 30% dimethyl sulfoxide and 70% saline. The treatments were initiated 9 days after the injection of the tumor cells. Mice were imaged the morning before the first injection to determine initial tumor size and then groups were organized to have equal distribution of tumor size before the initiation of the first injection. Mice were treated once a day for five days with temozoiornide. Mice were treated once a day, 5 days a week (Monday through Friday), with cannabinoids until the completion of the study, except for the first week of the study where mice were inject over the weekend. All mice were injected intraperitoneally.

[000283] Significant differences were determined using a one-way ANOVA. Bonferroni-Dunn post-hoc analyses were conducted when appropriate. Survival between groups was compared using a apian-Meier analysis and long-rank Mantel-Cox test or The Gehan-Bresiow-Wilcoxon test. P values <0,05 defined statistical significance,

[000284] A detailed explanation of Figure 8 is as follows. The X-axis represents the number of days after treatment and the Y-axis represents the survival rates.

[Θ00285] One of tumors in the vehicle group fully regressed overtime creating an outlier in the study. Tumor regression in a vehicle treated animal is a rare occurrence but it can occur. Since during the start of the study, the tumor did demonstrate a small increase in growth as assessed by I VIS imaging, it could not be removed from the data set. The data is presented with (Figure 8A) and without (Figure 8B) the outlier for comparison. With the vehicle outlier included, temozoiornide alone did not increase survival (p=0.48, Figure 8 A, p<0.05 is considered significant). Cannabidiol alone also did not increase survival. However, the combination of iemozolomide + 15 mg/kg of carmabidio! almost reached significance (p^::::0,09) for increasing survival using a Log- rank Mantel-Cox test, p<0.05 is considered significant. If this same data set was analyzed with the Gehan-Breslow-Wilcoxon test then the treatment of iemozolomide + eannabmoid did produce a significant increase in survival. The Gehan-Bresiow- Wilcoxon test however is a less stringent statistical test in comparison to the Log-rank Mantel-Cox test, it should be noted that 2 of the 1 1 mice are still alive in the iemozolomide -t- cannabinoid group, and in one of the mice the tumor has fully regressed based on in vivo imaging of the t umor.

[000286] If the vehicle outlier was removed from the data set, then treatment with iemozolomide significantly increased survival (p<0.5. Figure 8B). The combination of temozolomide + 15 mg/kg of cannabidiol, however was highly significant, at increasing survival (p^:::0.005). Thus, cannabidiol enhanced the antitumor activity of iemozolomide.

Example I Fharn¾a¾o¾h¾a ic Study 6fMtvltipIe Dose C'atthabidoj Oral Sol tion, in Pediatric Snht¾¾ $ with Trea:fei;ent~resis a«i Seizure Disorders

Protocol

[000287] A Phase 1/2, open label, Multiple Ascending Dose study will be conducted to evaluate the effect of multiple doses of cannabidiol oral solution on pediatric subjects experiencing treatment-resistant seizures. The study will assess pharmacokinetics, safety, tolerability and preliminary efficacy of 3 doses ( 10, 20, and 40 milligrams per kilogram per day ("mg/kg/day") of cannabidiol oral solution administered in a sequential fashion. Specifically, twenty subjects will be enrolled in each dose cohort that A) fit the following criteria: 1. subject and/or parent(s)/cafegi er(s) fully comprehend the informed consent form (ICF) and assent form, understand all study procedures, and can communicate satisfactorily with the Investigator and study coordinator; 2. provide informed consent and/or assent (as applicable) of subjects and/or parent(s)/caregiver(s) in accordance with applicable laws, regulations, and local requirements; 3, male or female between 1 and 17 years of age (inclusive) at the time of consent; 4. diagnosed with a treatment-resistant seizure disorder in the opinion of the Investigator and as defined as continued seizures despite; a. adequate trials of >3 antiepileptic drugs ("AEDs"), and b. >1 prior adequate treatment course with >2 AEDs in combination (i.e., concurrently); 5. willingness to remain on established AEDs (stable dosing for >30 days prior to Day 0 and throughout the duration of the study) a. neither a vagus nerve stimulation (VNS) procedure nor ketogenic diet are considered an AED for the purposes of this study; 6. willingness to not start a ketogenic diet during the Treatment Period or, if already on the diet, to make no changes in the diet during die study; 7. a female subject is eligible to participate in the study if she is: a, premenarchal, or b. of childbearing potential with a negative urine pregnancy test at the Screening Visit and at Day 0. If sexually active, she must agree to fulfill one of the following requirements: i. complete abstinence from intercourse >4 weeks prior to administration of the first dose of the investigational product, throughout the Treatment Period, and 4 weeks after completion or premature discontinuation from the investigational product, and agreement to use a double-barrier method if she becomes sexually active; ii. use of acceptable methods of contraception throughout the study and 4 weeks after completion or premature discontinuation from investigational product, The acceptable method of contraception is double barrier method (i.e., condom plus spermicide or a condom plus diaphragm): 8, a sexually active male subject must be willing to use acceptable methods of contraception throughout the study and for 4 weeks completion of study participation or premature discontinuation from investigational product. The acceptable methods of birth control are abstinence or double barrier birth control (i.e., condom plus spermicide or a condom plus diaphragm); 9. in the opinion of the Investigator, the parent(s)/caregiver(s) are willing and able to comply with the study procedures and visit schedules, including venipuncture, inpatient stay at the study center, dosing at the study center (twice a day as needed while an outpatient), and the Follow-up Visits (if applicable); 10, general good health (defined as the absence of any clinically relevant abnormalities as determined by the Investigator) based on physical and neurological examinations, medical history, and clinical laboratory values (hematology, chemistry, and urinalysis) completed during the Screening Visit: and 1 1 . body weight of > 9 kg; and B) do not meet the following criteria: 1. subject or parent(s)/caregiver(s) have daily commitments during the study duration that would interfere with attending all study visits; 2. currently taking concomitant medications that are strong cytochrome P450 3A4 ("CYP3A4") inhibitors or inducers or CYP3A4 sensitive substrates with a narrow therapeutic index; 3. currently taking any other disallowed medications: 4. currently taking felhamate if they had been receiving it for <6 months prior to the Screening Visit; 5. in the opinion of the Investigator, any clinically significant, unstable medical abnormality, chronic disease, or a history of a clinically significant abnormality of the cardiovascular, gastrointestinal, respiratory, hepatic, or renal systems; 6. any disorder or history of a condition (e.g., malabsorption or gastrointestinal surgery) that may interfere with drug absorption, distribution, metabolism, or excretion: 7. history or presence of abnormal electrocardiograms ("ECGs") that are clinically significant in the opinion of the Investigator; 8, for appropriate subjects, an affirmative answer to queries regarding active suicidal ideation with some intent to act. but without a specific plan or active suicidal ideation with specific plan and intent on the Columbia Suicide Severity Rating Scale ("C-SSRS") assessment at the Screening Visit, subjects who have significant findings for suicidal ideation as assessed by the C-SSRS must be referred to the investigator for follow-up evaluation; 9. any history of attempted suicide; 10. history of poor toleration of venipuncture or poor venous access that would cause difficulty in collecting blood samples; 1 1 , participation in any investigational study currently or within 30 days or 5 half-lives (t½) of the investigational product (whichever is longer) prior to the Screening Visit; 12. taken any cannabinoids (cannabidiol, Δ9- tetrahydrocannabmol [Δ9-ΊΉ€], hemp oil, Realm Oil or marijuana) in the 30 days prior to the Screening Visit; 13. history of an allergic reaction or a known or suspected sensitivity to any substance that is contained in the investigational product formulation; 14. known infection with hepatitis B. hepatitis C, or human immunodeficiency virus (HIV); 15, In the opinion of the investigator, the subject is unsuitable in any other way to participate in this study; and 16. body weight of >90 kg.

[000288] Each subject will be enrolled in only one dose cohort. No fewer than 2 subjects between 2 and 12 years of age must be dosed through Day 10 prior to dosing any subject <2 years of age, Each of the 3 planned dose cohorts will include 20 subjects for a study total of 60 subjects: 1 to <2 years of age: 5 subjects; 2 to <I2 years of age: 9 subjects with at least 3 under the age of 6; and 12 to <17 years of age: 6 subjects with at least 3 subjects under age 16. Each subject will complete a Screening Period of up to 28 days and a Treatment Period of 10 days. Subjects will have a Follow-up Visit on Day 14 and a Follow-up Phone Call on Day 17, On Day 1, the investigational product will be administered once in the morning according to the subject's assigned dose level cohort, The evening dose of the investigational product will not be administered on Day 1 . Thus, the subject will receive a half-daily dose only (5, 10, or 20 millgrams/kiiogram "mg/kg" total) of the investigational product on Day 1. Subjects will not receive a dose from Day 2 through Day 3 but they will remain in an inpatient setting and complete planned assessments. Subjects will be dosed twice daily (i.e., Ml daily dose of 10, 20. or 40 mg/kg/day) from Day 4 through Day 10 according to the subjects assigned cohort. Doses will be administered at approximately 12-hour intervals. Doses will be administered to subjects in a fasting state on days on which the serial. PK samples will be collected (i.e., Day 1 and Day 10.) Fasting times include i hour for ages 1 to less than 2 years and 2 hours for ages 2 to 17 years.

[000289] During the Screening, Treatment, and Follow-up Periods, subjects are not to receive the following: (1) medicaiion(s) that, are strong CYP3A4 inhibitors or inducers or CYP3A4-sensitive substrates with a narrow therapeutic index; (2) any cannabinoids (carmabidiol, A9-THC, hemp oil, Realm Oil or marijuana); corticotrophins; systemic steroid therapy (excluding inhaled medication for asthma treatment); ielbamate (if used for <6 months) or (7) any other investigational drug or investigational device. Subjects will remain on established ant epilepsy therapies (i.e., AE^'Ds for which dosing has been stable >30 days prior to Day 0) throughout the duration of the Treatment and Follow-up Periods.

[000290] in summary, for subjects ages 1 to <2 years, serial blood sampling for pharmacokinetic ("PK") analysis will occur at 2, 4, 8, and 12 hours post the Day 1 dose. Serial blood sampling for PK analysis will also occur at predose, 2, 4, 8, and 12 hours post the Day 10 morning dose, For subjects ages 2 to <6 years, serial blood sampling will occur at predose and at 1 , 2, 3, 4, 8, 12, 16, 24 (Day 2), and 48 (Day 3) hours post the Day 1 morning dose, Blood samples for PK trough values for cannabidiol and its 7- hydroxy ("OH") metabolite will be evaluated on Day 8. Collection will occur prior to the morning dose of the investigational product; no investigational product will be administered on Day 1 1. Serial blood sampling for PK analysis will also occur at predose, 1, 2, 3, 4, 8, 12, and 24 (Day 1 1) hours post the Day 10 morning dose. For subjects ages 6 to <17 years, serial blood sampling for PK analysis will occur predose and at 1 , 2, 3, 4, 6, 8, 12, 1 6, 24 (Day 2), 36 (Day 2), 48 (Day 3), and 72 (Day 4) hours post the Day 1 morning dose. Blood samples for PK trough values for cannabidiol and its 7-OH metabolite will be evaluated on Day 6 (age > 12 only), Day 8 and Day 9, Collection will occur prior to the morning dose of the investigational product; no investigational product will be administered on Day 1 1. Serial blood sampling for PK analysis will also occur at predose and at 1 , 2, 3, 4, 6, 8, 12, and 24 (Day 1 1) hours post the Day 10 morning dose. In addition to the above measurements of cannabidiol and its 7-OH metabolite, levels of clobazani and norclobazam will be measured from the samples taken predose on Day 1 (baseline), Day 8, and Day 10 (predose) for subjects who are aged >2 years and are currently taking clobazam.

Endpoints

[000291] Endpoints of the study will include the following: (1) Incidence, type, and severity of adverse events ("AEs") and serious adverse events ("SAEs") occurring during the Treatment Period (i.e., treatment-emergent adverse events ["TEAEs"]); (2) Changes from, baseline in vital signs; (3) Changes from baseline in ECG findings; (4) Changes from baseline in laboratory values (hematology, chemistry, and urinalysis); (5) Plasma PK variables for cannabidiol (parent compound) and its 7-OH metabolite as appropriate: (a) Maximum plasma concentration (Cmax) and dose normalized Cmax (G ^'D) (b) time to Cmax (tfr.sx); (c) Half-life (tj 2); (d) Elimination rate; (e) Oral clearance (cannabidiol only); (f) Volume of distribution (cannabidiol only); (g) Area under the plasma concentration-time curve from 0 to 12 hours [AUC(o-i2)j and dose normalized AU o-12) [AUC(o-i2_.)/D] on Day 1 ; (h) Area under curve from time 0 to the last quantifiable concentration [AU o-iast)] on Day 1 : (i) Area under the plasma concentration-time curve from 0 to infinity (AUQo-mn) and dose normalized AUQo-inf) [AUC(o-inf)/Dj on Day 1 for study subjects >2 years of age; (j) Metabolite to parent ratios for Cmax, AUC o-ino_> AU o- 12) on Day 1 and Day 10; (k) AUC(o-i2> and AUQo-i D on Day 10; (1) Minimum plasma concentration (Cmin) on Day 1 0; (m) Average plasma concentration (Cavg) on Day 10; (n) Accumulation ratios for Cmax and AUQ0-12) on Day 10; (o) Time linearity; (6) clinical global impressions of improvement ("CGi-i") assessment on Day 1 1 ; and (7) Change from baseline in clinical global impressions of severity ("CGI-S") assessment from the Screening Visit to Day 1 1.

Safety

[000292] Subjects will be assessed by measurement of vital signs and neurological examination daily. A Physical Examination will be completed at the Screening Visit, as well as Day 0, Day 1 1 and Day 14, A 12-lead ECG, will be completed at the Screening Visit, as well as Day 1, Day 4, Day 8, Day 11. and Day 14 (if clinically indicated). Hematology, chemistry, and urine analysis will be performed at the Screening Visit, as well as Day 1 , Day 4, Day 8, and Day 11. Hematology, chemistry, and urine analysis vvili also be performed on Day 14 if clinically indicated,

Methods

[000293] The PK concentrations and parameters for cannabidioi and its 7-OH metabolite in plasma will be summarized by study day. sampling time (where appropriate) and dose using descriptive statistics and graphic displays as appropriate. These results will be graphically displayed by age and nig/kg dose, as appropriate, Exposure relationship with age and body weight will be evaluated using regression and/or inferential analyses, as appropriate. Dose proportionality of cannabidioi and its 7-OH metabolite exposure will be investigated using graphical methods and statistically using a power model approach, as appropriate. Accumulation of cannabidioi and its 7-OH metabolite vvili be assessed using an appropriate analysis of variance model for exposure PK parameters. Time linearity will also be assessed. Trough concentrations samples collected prior to dosing at the scheduled time points will be assessed graphically for attainment of steady state. Also, time to reach steady state will be assessed with a stepwise linear trend analysis. Levels of clobazam and norclobazam will be measured from the samples taken predose on Day 1 (baseline), Day 8, and Day 10 (predose) for subjects who are age > 2 and currently taking clobazam and summarized by time point, and treatment, All safety assessments, including AEs, clinical laboratory evaluations, vital signs, 12-lead ECGs, C-SSRS, and physical and neurological examinations will be listed. When appropriate, they will be summarized with descriptive statistics by age and dose cohort, The results of the CGi-L CGI-S, and daily seizure diary assessments will be summarized by descriptive statistics as appropriate.

Results

[000294] Preliminary results are shown in Table 61 below. Cohort #1 was administered a single dose of 5 mg/kg of an alcohol based formulation and then 5 mg kg BID (10 mg/kg/day) for 7 days, Cohort #2 was administered a single dose of 10 mg/kg of a lipid based formulation and then 10 mg/kg BID (20 mg/kg/day) for 7 days. For cohort #1 single dosing resulted in a mean C_max of 59.029 ng/mL, mean T_max of 3.0 hours and an AUCinf of 276,95 h*ng mL. For cohort #2 single dosing resulted in a mean C of 1 10,522 ng/mL, mean T_max of 4.45 hours and an AUCinf of 879.273 h*ng mL. As demonstrated, lipid based formulations at twice the dosage and at a single dosing achieved nearly twice the maximum plasma concentration of the alcohol based formulations in nearly an hour and half longer.

[000295] At repeated BID dosing, administration of alcohol based oral cannabinoid formulations resulted in a mean C_ma of 1 1 .6 ng mL, mean Tmax of 2.75 hours and an AUCtau of 581.744 h*ng mL and the lipid based or al cannabinoid formulations resulted in a Cmax of 214.28 ng/mL, mean I mris of 2.55 hours and an AUCtau of 1 135.345 h*ng/mL, As demonstrated, lipid based formulations at twice the dosage and at administered BID for 7 days achieved less than twice the maximum plasma concentration of the alcohol based formulat ons twelve minutes faster.

Table 61. Pharmacokinetic Parameters for Oral Cannabinoid Solutions

: Cohort 20 20 ;! 12 ! N 20 20 j: 1 8 j

Example 17, F aonacokinetic Foc?d- fl¾ct Jlfed-V of Single Dose Caima do Oral §ol¾i:k¾ in i kai hy S ibjeets

[000296] An open label, randomized, single-dose, two-period, two-way crossover food-effect study is being conducted on healthy subjects. The study assesses pharmacokinetics and safety of single-dose of 20 rng/kg/day administered under fasted or fed conditions. Specifically, twenty-four subjects were enrolled in each treatment arm. For this preliminary pharmacokinetic analysis, nominal time and default lambda-z selections were used. All below quantifiable limit values were set to zero and all subjects were included in the analysis. Preliminary pharmacokinetic analysis suggests that consumption of food with oral cannabidiol solutions of the present invention favorably impact pharmacokinetic parameters.

Claims

A stable pharmaceutical formulation for oral administration comprising:

from about 0.1 to about 40 % of a carmabinoid; and from about 10 to about. 95 % of a lipid.

The formulation of claim 1 wherein the lipid is selected from the group consisting of sesame oil, olive oil, corn oil, sunflower oil, safflower oil, flaxseed oil, almond oil, peanut oil, walnut oil, cashew oil, castor oil, coconut oil, palm oil, soybean oil, canola oil, vegetable oil. rice bran oil. caproic acid, enanthie acid, caprylic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, pentadecyiic acid, palmitic acid, margaric acid, oleic acid, stearic acid, nonadecylic acid, linoleic acid, arachidie acid and araehidonic acid, medium chain glycerides, decanoyl glycerides, octanoyl glycerides, caprylic/capric triglyceride, oleoyl polyoxyl-6 glycerides, linoleoyi polyoxyl-6 glycerides, polyglyceryl-3 dioleate, glyceryl monolinoieate, glyceryl monocaprylate, oleic acid, and a combination thereof

The formulation of claim 1 wherein the cannabinoid is selected from group consisting of eannabmol, cannabidiol, dronabinol (de!ta-9-tetrahydrocannabinoi), delta-8-tetrahydrocamiabinol, 1 1 -hydroxy-tetrahydrocannabinol, 1 1-hydroxy- delta9-tetrahydrocannabinol, Ievonantradol, delta- 1 1 -tetrahydrocannabinol, tetrahydrocannahivarin, amandamide, nabilone, acids, analogs, and synthetic derivatives thereof.

The formulation of claim 3 wherein the cannabinoid is cannabidiol.

The formulation of claim 4 wherein the cannabidiol is substantially pure, synthetically synthesized, cannabidiol which has a purity greater than 98 %.

The formulation of claim 1 wherein the formulation is free of alcohol.

The formulation of claim 1 further comprising from about 3 % to about 15 % ethanol.

8. The formiilaiion of claim 7 wherein ihe ethanol is at a concentration from about 1 % to about 10 %,

9. The formulation of claim 1 further comprising from about 0.001 % to about 1 % of an antioxidant,

10. The formulation of claim 9 wherein the antioxidant is selected from the group consisting of butylated hydroxyltoluene, butylated hydroxyl anisole, a!pha- tocopherol (Vitamin E). ascorbyl palmitate, ascorbic acid, sodium aseorbate, ethylenediamino tetraacetic acid (EDTA), cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate, sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, monothioglycerol, teri-butylhydroquinone and combinations thereof.

11. The formulation of claim 10 wherein the antioxidant is selected from the group consisting of butylated hydroxyltoluene, butylated hydroxyl anisole. alpha tocopherol (Vitamin E), ascorbyl palmitate, propyl gallate, EDTA_S tert- butylhydroquinone and a combination thereof.

12. A stable pharmaceutical formulation for oral administration comprising:

from about 5 % to about 40 % of cannabidioi; and

from about 10 to about 74 % of a medium chain glyceride.

13. The formulation of claim 12 wherein the formulation is free of alcohol.

14. The formulation of claim 12 further comprising from about 1 % to about 15 % ethanol.

15. The formulation of claim 12 further comprising from about 0.1 % to about 1.0 % of an antioxidant selected from the group consisting of alpha-tocopherol (Vitamin E), ascorbyl palmitate, and a combination thereof

16. The form ulati on of c I aim 12 wherein :

the cannabidioi is at a concentration of from about 28 % to about 32 %; the medium chain triglyceride is at a concentration from about 66 % to about 74 %.

17. The formulation of claim 16, wherein the medium chain triglyceride is a caprylk 'eapric triglyceride.

18. A stable pharmaceutical formulation for oral administration comprising:

cannabidiol at a concentration of about 31.09 %; and

captylic/capric triglyceride at a concentration of about 68.4%

19. The formulation of claim 18 further comprising about 0.20% alpha-tocophe.ro I. (Vitamin E).

20. A method for treating a disease or disorder, or a symptom of a disease or disorder, comprising administering the formulation of claim 1 to a patient in need thereof, wherein the disease or disorder is selected from the group consisting of Prader- Willi syndrome, obesity, graft versus host disease, gelastie seizures/hypothalamic hamartoma, neonatal seizures, movement disorders including dystonia, central pain syndromes, phantom limb pain, multiple sclerosis, traumatic brain injury, radiation therapy, acute and chronic graft versus host disease, T-cell autoimmune disorders, colitis, Dravet Syndrome, Lennox Gastaut Syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, posttraumatic stress disorder, anxiety, early psychosis, Alzheimer's Disease, autism, acne, Parkinson's disease, social anxiety disorder, depression, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic injury of heart, ischemic injury of brain, chronic pain syndrome, and rheumatoid arthritis.

21. The method of claim 20, wherein the patient is in a fed or fasted condition.

22. A method for assisting with withdrawal from opioids, cocaine, heroin, amphetamines or nicotine comprising administering the formulation of claim 1 to a patient in need thereof.